A Novel Running Wheel Mouse Model for Botulism and its use for the Evaluation of Post-Symptom Antitoxin Efficacy

Antitoxin is currently the only approved therapy for botulinum intoxications. The efficacy of antitoxin preparations is evaluated in animals. However, while in practice antitoxin is administered to patients only after symptom onset, in most animal studies, it is tested in relation to time post intoxication. This may be attributed to difficulties in quantitating early botulism symptoms in animals. In the current study, a novel system based on high-resolution monitoring of mouse activity on a running wheel was developed to allow evaluation of post-symptom antitoxin efficacy. The system enables automatic and remote monitoring of 48 mice simultaneously. Based on the nocturnal activity pattern of individual naïve mice, two criteria were defined as the onset of symptoms. Post-symptom treatment with a human-normalized dose of antitoxin was fully protective in mice exposed to 4 LD50 of BoNT/A and BoNT/B. Moreover, for the first time, a high protection rate was obtained in mice treated post-symptomatically, following a challenge with BoNT/E, the fastest acting BoNT. The running wheel system was further modified to develop a mouse model for the evaluation of next-generation therapeutics for progressive botulism at time points where antitoxin is not effective. Exposure of mice to 0.3 LD50 of BoNT/A resulted in long-lasting paralysis and a reduction in running activity for 16-18 days. Antitoxin treatment was no longer effective when administered 72 hr post intoxication, defining the time window to evaluate next-generation therapeutics. Altogether, the running wheel systems presented herein offer quantitative means to evaluate the efficacy of current and future anti-botulinum drugs.

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Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

International Journal of Molecular Sciences ◽

10.3390/ijms22052479 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2479

Author(s):

Amir Mohammadzadeh ◽

Péter P. Lakatos ◽

Mihály Balogh ◽

Ferenc Zádor ◽

Dávid Árpád Karádi ◽

...

Keyword(s):

Neuropathic Pain ◽

Animal Studies ◽

Acute Administration ◽

Pain Model ◽

Therapeutic Value ◽

Small Doses ◽

Function Test ◽

Neuropathic Pain Model ◽

First Time ◽

Glycine Content

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.

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Recurrence time distribution and temporal clustering properties of a cellular automaton modelling landslide events

Nonlinear Processes in Geophysics ◽

10.5194/npg-20-1071-2013 ◽

2013 ◽

Vol 20 (6) ◽

pp. 1071-1078 ◽

Cited By ~ 1

Author(s):

E. Piegari ◽

R. Di Maio ◽

A. Avella

Keyword(s):

Time Series ◽

Probability Distribution ◽

Cellular Automaton ◽

Time Window ◽

Fano Factor ◽

Recent Analysis ◽

Recurrence Time ◽

Model Parameters ◽

Reasonable Prediction ◽

First Time

Abstract. Reasonable prediction of landslide occurrences in a given area requires the choice of an appropriate probability distribution of recurrence time intervals. Although landslides are widespread and frequent in many parts of the world, complete databases of landslide occurrences over large periods are missing and often such natural disasters are treated as processes uncorrelated in time and, therefore, Poisson distributed. In this paper, we examine the recurrence time statistics of landslide events simulated by a cellular automaton model that reproduces well the actual frequency-size statistics of landslide catalogues. The complex time series are analysed by varying both the threshold above which the time between events is recorded and the values of the key model parameters. The synthetic recurrence time probability distribution is shown to be strongly dependent on the rate at which instability is approached, providing a smooth crossover from a power-law regime to a Weibull regime. Moreover, a Fano factor analysis shows a clear indication of different degrees of correlation in landslide time series. Such a finding supports, at least in part, a recent analysis performed for the first time of an historical landslide time series over a time window of fifty years.

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First-principles study of the structural, optoelectronic and thermophysical properties of the π-SnSe for thermoelectric applications

Beilstein Journal of Nanotechnology ◽

10.3762/bjnano.12.82 ◽

2021 ◽

Vol 12 ◽

pp. 1101-1114

Author(s):

Muhammad Atif Sattar ◽

Najwa Al Bouzieh ◽

Maamar Benkraouda ◽

Noureddine Amrane

Keyword(s):

Thermoelectric Properties ◽

Density Functional ◽

Practical Importance ◽

Next Generation ◽

Thermoelectric Devices ◽

Functional Theory ◽

Tin Selenide ◽

Large Lattice ◽

The Density Functional Theory ◽

First Time

Tin selenide (SnSe) has thermoelectric (TE) and photovoltaic (PV) applications due to its exceptional advantages, such as the remarkable figure of merit (ZT ≈ 2.6 at 923 K) and excellent optoelectronic properties. In addition, SnSe is nontoxic, inexpensive, and relatively abundant. These aspects make SnSe of great practical importance for the next generation of thermoelectric devices. Here, we report structural, optoelectronic, thermodynamic, and thermoelectric properties of the recently experimentally identified binary phase of tin monoselenide (π-SnSe) by using the density functional theory (DFT). Our DFT calculations reveal that π-SnSe features an optical bandgap of 1.41 eV and has an exceptionally large lattice constant (12.2 Å, P213). We report several thermodynamic, optical, and thermoelectric properties of this π-SnSe phase for the first time. Our finding shows that the π-SnSe alloy is exceptionally promising for the next generation of photovoltaic and thermoelectric devices at room and high temperatures.

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Injection of next-generation directly-induced neural stem cells (iNSCs) induces recovery in a mouse model of multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2014.08.520 ◽

2014 ◽

Vol 275 (1-2) ◽

pp. 193 ◽

Cited By ~ 1

Author(s):

Luca Peruzzotti-jametti ◽

Giulia Mallucci ◽

Gillian Tannahill ◽

Bing Huang ◽

Yenal Bernard Lakes ◽

...

Keyword(s):

Multiple Sclerosis ◽

Stem Cells ◽

Mouse Model ◽

Neural Stem Cells ◽

Next Generation ◽

Induced Neural Stem Cells

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A New Formulation for the Dial-a-Ride Problem

Transportation Science ◽

10.1287/trsc.2021.1044 ◽

2021 ◽

Author(s):

Yannik Rist ◽

Michael A. Forbes

Keyword(s):

Time Window ◽

Valid Inequalities ◽

Route Planning ◽

Branch And Cut ◽

Mixed Integer ◽

Planning Problem ◽

Current State ◽

New Formulation ◽

First Time ◽

Delivery Location

This paper proposes a new mixed integer programming formulation and branch and cut (BC) algorithm to solve the dial-a-ride problem (DARP). The DARP is a route-planning problem where several vehicles must serve a set of customers, each of which has a pickup and delivery location, and includes time window and ride time constraints. We develop “restricted fragments,” which are select segments of routes that can represent any DARP route. We show how to enumerate these restricted fragments and prove results on domination between them. The formulation we propose is solved with a BC algorithm, which includes new valid inequalities specific to our restricted fragment formulation. The algorithm is benchmarked on existing and new instances, solving nine existing instances to optimality for the first time. In comparison with current state-of-the-art methods, run times are reduced between one and two orders of magnitude on large instances.

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Abstract 285: Osteopontin Deficiency Ameliorates Heart Failure with Preserved Ejection Fraction Pathology by Upregulating Mitochondrial 2-Oxoglutarate Dehydrogenase Like Enzyme

Circulation Research ◽

10.1161/res.121.suppl_1.285 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Keyvan Yousefi ◽

Wen Ding ◽

Lina A Shehadeh

Keyword(s):

Mouse Model ◽

Diastolic Dysfunction ◽

Interstitial Fibrosis ◽

Matricellular Protein ◽

Double Knockout ◽

Protein Levels ◽

Lower Protein ◽

Myocardial Energetics ◽

First Time

HFpEF is an increasingly prevalent syndrome associated with impaired myocardial energetics, for which no etiologic therapy is available. Osteopontin (OPN) is a matricellular protein that is upregulated in the circulation of HFpEF patients, and reported to induce mitochondrial stress in rodent cardiomyocytes. Here we evaluate the role of circulating OPN in regulating myocardial function in the nephrotic Col4a3 -/- mouse model of HFpEF. We performed extensive cardiac, biochemical and mitochondrial analyses of the Col4a3 -/- mouse and found a striking HFpEF phenotype. We showed OPN levels were elevated in Col4a3 -/- mice (FC=2.1, n=6; p<.01). Col4a3 -/- mice were hypertensive, had diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis - all of which were ameliorated in Col4a3 -/- OPN -/- mice (n=5-20; p<.05). Col4a3 -/- hearts had dysmorphic mitochondria (EM), lowered antioxidant capacity as a 50% reduction in GSH/GSSG ratio (n=6; p<.05) and lower protein levels of mitochondrial respiratory complexes I, II and IV (p<.05). Flux assay in adult cardiomyocytes showed that maximal respiration was reduced in Col4a3 -/- hearts (575.84±37.6 vs 322.34±25.48 pmol/min in WT, n=9; p<.0001). Microarray data (validated by mitochondrial blot) implicated OGDHL as decreased in Col4a3 -/- hearts but increased in double knockout Col4a3 -/- OPN -/- hearts compared to WT (n=3; p<.05). OGDH activity was also lower in Col4a3 -/- hearts (17.1±7.3 vs 2.5±1.1 mU/mg in WT; n=6; p<.05). In Col4a3 -/- mice, heart-specific AAV9-mediated overexpression of OGDHL, similar to global OPN KO, improved survival by ~50-100% (p<.0001). Isovolumetric relaxation time, a marker of diastolic dysfunction, which is prolonged in Col4a3 -/- mice (26.17 vs 15.30±1 ms, n=26; p<.001) was decreased in Col4a3 -/- OPN -/- mice (18.1±1 ms, n=37; p<.01) as well as in AAV9-cTnT-OGDHL-treated Col4a3 -/- mice (16.7±2.5 ms, n=8; p<.05). In conclusion, we present a new mouse model for HFpEF in which diastolic function and lifespan can be improved by genetic deletion of OPN or cardiac OGDHL gene therapy. Our results elucidate for the first time the pivotal roles of circulating OPN and cardiac OGDHL in HFpEF pathophysiology and present two related potential therapeutic targets for HFpEF.

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Global scientific output trend for Akkermansia muciniphila research: a bibliometric and scientometric analysis

BMC Medical Informatics and Decision Making ◽

10.1186/s12911-020-01312-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hojat Dehghanbanadaki ◽

Hossein Aazami ◽

Shahrbanoo Keshavarz Azizi Raftar ◽

Fatemeh Ashrafian ◽

Hanieh-Sadat Ejtahed ◽

...

Keyword(s):

Animal Studies ◽

The United States ◽

Detection Algorithm ◽

Scientific Output ◽

Subject Area ◽

Scientometric Analysis ◽

Akkermansia Muciniphila ◽

Type2 Diabetes ◽

First Time ◽

Bibliometric Profile

Abstract Background Akkermansia muciniphila is an anaerobic bacterium residing in the healthy intestinal tract of host and its quantity has a negative correlation with various host diseases. This study for the first time provides a holistic bibliometric aspect of Akkermansi muciniphila research in the literature and shows the hot topic terms of these articles in any period of time. Methods Scopus database was selected to retrieve documents relevant to Akkermansia muciniphila in any language up to 2019. The bibliometric profile of Akkermansia muciniphila articles including subject area, year distribution, citations, institutions, journals, authors, and countries was systematically characterized and the collaboration networks of authors and countries as well as the burst detection algorithm of the words in the titles, abstracts and keywords were visualized. Results There is a progressive growing trend in research on Akkermansia from 2004 to 2019 with a total of 566 articles during this period. Out of 353 original articles, there are 194 animal studies (155 studies on mice) and 112 human studies. Also, 65 various diseases were investigated in these studies. The most focused conditions are obesity (71 articles) and type2 diabetes (39 articles). The United States is the leading country on Akkermansia publications (n = 132), followed by China (n = 95). Frontiers in Microbiology is the most dominant journal with 23 Akkermansia publications. In addition, “cancer” is the hot topic of recent Akkermansia research. Conclusion Akkermansia research is of progressive interest during the last decade and the studies on this subject move towards its relationship with cancer and its promising effect on health.

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First building engineers in architectural practice of St. Petersburg at the beginning of the 19th century

E3S Web of Conferences ◽

10.1051/e3sconf/202016405011 ◽

2020 ◽

Vol 164 ◽

pp. 05011

Author(s):

Ekaterina Vozniak ◽

Svetlana Golovina ◽

Maria Kolesova

Keyword(s):

Civil Engineer ◽

Urban Development ◽

Engineering Education ◽

19Th Century ◽

Building Structures ◽

Next Generation ◽

Bridge Construction ◽

Architectural Practice ◽

The 19Th Century ◽

First Time

The emergence of the specialty of civil engineer in the first half of the 19th century had a significant impact on architectural practice in St. Petersburg. The differentiation of the professions of engineer and architect took place for the first time; both specialists began to participate in the design. The appearance of such engineers as Augustine Betancourt, Matvey Clark, Pierre-Dominique Bazin and Wilhelm von Tretter brought about changes in all areas of architecture and construction. New building structures and materials appeared, as well as methods for checking and calculating. Designing has become comprehensive, the activities of the Committee for Structures and Hydraulic Works led by Betancourt covered urban development, individual buildings and all types of utilities. The formation of engineering education took place, which brought up the next generation of Russian engineers.The article considers the most important aspects of the activities of Augustine Betancourt, who laid the foundations for engineering education in Russia; Matvey Clark, who created the first metal beams and trusses; Pierre Dominique Bazin, who continued the development of engineering education, as well as Wilhelm von Tretter, one of the founders of iron bridge construction in Russia.

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Nme1 and Nme2 genes exert metastasis-suppressor activities in a genetically engineered mouse model of UV-induced melanoma

British Journal of Cancer ◽

10.1038/s41416-020-01096-w ◽

2020 ◽

Vol 124 (1) ◽

pp. 161-165

Author(s):

Nidhi Pamidimukkala ◽

Gemma S. Puts ◽

M. Kathryn Leonard ◽

Devin Snyder ◽

Sandrine Dabernat ◽

...

Keyword(s):

Mouse Model ◽

Suppressor Gene ◽

Genetically Engineered ◽

In Vivo Model ◽

Metastasis Suppressor ◽

Specific Context ◽

Genetically Engineered Mouse Model ◽

Metastatic Activity ◽

First Time

AbstractNME1 is a metastasis-suppressor gene (MSG), capable of suppressing metastatic activity in cell lines of melanoma, breast carcinoma and other cancer origins without affecting their growth in culture or as primary tumours. Herein, we selectively ablated the tandemly arranged Nme1 and Nme2 genes to assess their individual impacts on metastatic activity in a mouse model (HGF:p16−/−) of ultraviolet radiation (UVR)-induced melanoma. Metastatic activity was strongly enhanced in both genders of Nme1- and Nme2-null mice, with stronger activity in females across all genotypes. The study ascribes MSG activity to Nme2 for the first time in an in vivo model of spontaneous cancer, as well as a novel metastasis-suppressor function to Nme1 in the specific context of UVR-induced melanoma.

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ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20205151 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5151 ◽

Cited By ~ 1

Author(s):

Norante ◽

Peggion ◽

Rossi ◽

Martorana ◽

De Mario ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Nervous System Function ◽

Serca Pump ◽

Selective Death ◽

First Time ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

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