Investigating the mechanisms of action of VGF-derived peptides in the nervous system

The VGF neurosecretory protein, first identified as a nerve growth factor (NGF) inducible gene product, is selectively synthesised predominantly in neuronal and neuroendocrine cells. The ~68 kDa VGF protein sequence is rich in paired basic amino acids, and thus the protein undergoes endoproteolytic cleavage to produce smaller peptides, which are stored in dense core vesicles and released upon stimulation via the regulated secretory pathway both in vitro and in vivo. Several of these VGF-derived peptides have been characterised and are involved in energy homeostasis, reproductive processes, synaptic plasticity as well as pain modulation. A number of studies have observed an increase in VGF gene expression in various pain models and more recently the VGF-derived peptides, TLQP-21, LQEQ-19 and TLQP-62 showed direct modulation of inflammatory and neuropathic pain when applied in vivo. The molecular mechanisms of action of VGF-derived peptides are not well understood and were investigated in this study. The TLQP-21 peptide, but not LQEQ-19, was shown to dose-dependently induce an increase in intracellular Ca2+ levels from cellular internal stores in brain- and spinal cord-derived primary microglia, in >65 % of the cell population in vitro. Three hour treatment of primary microglia with TLQP-21 (100 nM) induced a 2.78 fold increase in Ccl11 and a 2.28 fold decrease in Cxcl9 gene expression levels relative to the vehicle control (Student's t-test; p ≤ 0.05). Biochemical analysis using affinity chromatography and LC-MS/MS techniques identified the gC1q-R protein as a potential binding partner / receptor for TLQP-21. The gC1q-R protein is a ubiquitously expressed, multi-compartmental protein involved in complement activation, inflammatory processes and the plasma bradykinin formation pathway. These results tentatively suggest that TLQP-21 may contribute to the modulation of pain through activation of primary microglia and potentially involve interactions with components of the complement system. The findings highlight the importance of VGF-derived peptides in pain research and could lead to new perspectives and targets for pain therapeutics

Fulminant invasive aspergillosis of the mediastinum in an immunocompetent host: a case report

Introduction: Invasive aspergillosis is a serious complication in immunocompromised patients. It is an opportunistic disease, which predominantly occurs in the lungs, although dissemination to virtually any organ is possible. Invasive aspergillosis in an immunocompetent patient with extension to the mediastinum has rarely been reported. Here, we present the case of a patient with no apparent immunodeficiency state, who presented with Aspergillus endocarditis and fulminant invasive aspergillosis with extensive involvement of the mediastinal structures, which ultimately was responsible for her death. To the best of our knowledge, this is the first reported case in the literature on fulminant invasive mediastinal aspergillosis with extension to the pulmonary vasculature and concomitant Aspergillus endocarditis in an apparently immunocompetent patient without pre-existing lung disease. Case presentation: Our patient was a previously healthy 47-year-old Asian woman, who presented to our emergency room with severe progressive shortness of breath of one month’s duration, associated with orthopnea and unstable vital signs. Conclusion: Invasive aspergillosis has been described in the presence of pulmonary disease, such as chronic obstructive pulmonary disorder, and one case has been reported in a patient without preexistent disease, but none of these have been fatal. Our case is therefore the first reported case of its kind. Our case shows that fulminant aspergillosis can occur in an immunocompetent host and can be fatal. We conclude that invasive aspergillosis should not be excluded from the differential diagnosis on the basis of immunocompetency

Fulminant invasive aspergillosis of the mediastinum in an immunocompetent host: a case report.

Introduction: Invasive aspergillosis is a serious complication in immunocompromised patients. It is an opportunistic disease, which predominantly occurs in the lungs, although dissemination to virtually any organ is possible. Invasive aspergillosis in an immunocompetent patient with extension to the mediastinum has rarely been reported. Here, we present the case of a patient with no apparent immunodeficiency state, who presented with Aspergillus endocarditis and fulminant invasive aspergillosis with extensive involvement of the mediastinal structures, which ultimately was responsible for her death. To the best of our knowledge, this is the first reported case in the literature on fulminant invasive mediastinal aspergillosis with extension to the pulmonary vasculature and concomitant Aspergillus endocarditis in an apparently immunocompetent patient without pre-existing lung disease. Case presentation: Our patient was a previously healthy 47-year-old Asian woman, who presented to our emergency room with severe progressive shortness of breath of one month’s duration, associated with orthopnea and unstable vital signs. Conclusion: Invasive aspergillosis has been described in the presence of pulmonary disease, such as chronic obstructive pulmonary disorder, and one case has been reported in a patient without preexistent disease, but none of these have been fatal. Our case is therefore the first reported case of its kind. Our case shows that fulminant aspergillosis can occur in an immunocompetent host and can be fatal. We conclude that invasive aspergillosis should not be excluded from the differential diagnosis on the basis of immunocompetency

HPV16 E1^E4 protein is phosphorylated by Cdk2/cyclin A and relocalizes this complex to the cytoplasm

AbstractThe human papillomavirus type 16 E1^E4 protein is expressed abundantly in cells supporting viral DNA amplification, but its expression is lost during malignant progression. In cell culture, 16E1^E4 causes G2 cell cycle arrest by associating with and preventing the nuclear entry of Cdk1/cyclin B1 complexes. Here, we show that 16E1^E4 is also able to associate with cyclin A and Cdk2 during the G2 phase of the cell cycle. Only a weak association was apparent during S-phase, and progression through S-phase appeared unaffected. As with cyclin B1, the interaction of 16E1^E4 with cyclin A is dependent on residues T22/T23 and results in the accumulation of cyclin A in the cytoplasm where it colocalizes with 16E1^E4. 16E1^E4 serine 32 was found to be phosphorylated by Cdk2/cyclin A. We hypothesize that the interaction of 16E1^E4 with cyclin A may serve to increase the efficiency with which 16E1^E4 is able to prevent mitotic entry

Mechanochemical Ni-Catalysed Arylation of Ortho-Hydroxyarylenaminones : Synthesis of Isoflavones

This work describes two new synthetic methods for the preparation of isoflavones following the Ni-catalysed domino arylation reactions of the vast range of ortho-hydroxyarylenaminones utilising aromatic bromides as well as carboxylic acids. The presented protocols tolerated significant variation of all coupling partners and enabled synthesis of isoflavone library of twenty-three representatives. This is the first communicated precedent where the mechanic energy was utilised in the synthesis of isoflavones following the domino cyclisation mode.Peer reviewe

Linear Diophantine Fuzzy Rough Sets: A New Rough Set Approach with Decision Making

In this article, a new hybrid model named linear Diophantine fuzzy rough set (LDFRS) is proposed to magnify the notion of rough set (RS) and linear Diophantine fuzzy set (LDFS). Concerning the proposed model of LDFRS, it is more efficient to discuss the fuzziness and roughness in terms of linear Diophantine fuzzy approximation spaces (LDFA spaces); it plays a vital role in information analysis, data analysis, and computational intelligence. The concept of (,)-indiscernibility of a linear Diophantine fuzzy relation (LDF relation) is used for the construction of an LDFRS. Certain properties of LDFA spaces are explored and related results are developed. Moreover, a decision-making technique is developed for modeling uncertainties in decision-making (DM) problems and a practical application of fuzziness and roughness of the proposed model is established for medical diagnosis

Current challenges of digital health interventions in Pakistan: Mixed methods analysis

Background: Digital health is well-positioned in low and middle-income countries (LMICs) to revolutionize health care due, in part, to increasing mobile phone access and internet connectivity. This paper evaluates the underlying factors that can potentially facilitate or hinder the progress of digital health in Pakistan.Objective: The objective of this study is to identify the current digital health projects and studies being carried out in Pakistan, as well as the key stakeholders involved in these initiatives. We aim to follow a mixed-methods strategy and to evaluate these projects and studies through a strengths, weaknesses, opportunities, and threats (SWOT) analysis to identify the internal and external factors that can potentially facilitate or hinder the progress of digital health in Pakistan.Methods: This study aims to evaluate digital health projects carried out in the last 5 years in Pakistan with mixed methods. The qualitative and quantitative data obtained from field surveys were categorized according to the World Health Organization\u27s (WHO) recommended building blocks for health systems research, and the data were analyzed using a SWOT analysis strategy.Results: Of the digital health projects carried out in the last 5 years in Pakistan, 51 are studied. Of these projects, 46% (23/51) used technology for conducting research, 30% (15/51) used technology for implementation, and 12% (6/51) used technology for app development. The health domains targeted were general health (23/51, 46%), immunization (13/51, 26%), and diagnostics (5/51, 10%). Smartphones and devices were used in 55% (28/51) of the interventions, and 59% (30/51) of projects included plans for scaling up. Artificial intelligence (AI) or machine learning (ML) was used in 31% (16/51) of projects, and 74% (38/51) of interventions were being evaluated. The barriers faced by developers during the implementation phase included the populations\u27 inability to use the technology or mobile phones in 21% (11/51) of projects, costs in 16% (8/51) of projects, and privacy concerns in 12% (6/51) of projects.Conclusions: We conclude that while digital health has a promising future in Pakistan, it is still in its infancy at the time of this study. However, due to the coronavirus disease 2019 (COVID-19) pandemic, there is an increase in demand for digital health and implementation of health outcomes following global social distancing protocols, especially in LMICs. Hence, there is a need for active involvement by public and private organizations to regulate, mobilize, and expand the digital health sector for the improvement of health care systems in countries

Surveillance of molecular markers of antimalarial drug resistance in Plasmodium falciparum and Plasmodium vivax in Federally Administered Tribal Area (FATA), Pakistan

This molecular epidemiological study was designed to determine the antimalarial drug resistance pattern, and the genetic diversity of malaria isolates collected from a war-altered Federally Administered Tribal Area (FATA), in Pakistan. Clinical isolates were collected from Bajaur, Mohmand, Khyber, Orakzai and Kurram agencies of FATA region between May 2017 and May 2018, and they underwent DNA extraction and amplification. The investigation of gene polymorphisms in drug resistance genes (dhfr, dhps, crt, and mdr1) of Plasmodium falciparum and Plasmodium vivax was carried out by pyrosequencing and Sanger sequencing, respectively. Out of 679 PCR-confirmed malaria samples, 523 (77%) were P. vivax, 121 (18%) P. falciparum, and 35 (5%) had mixed-species infections. All P. falciparum isolates had pfdhfr double mutants (C59R+S108N), while pfdhfr/pfdhps triple mutants (C59R+S108N+A437G) were detected in 11.5% of the samples. About 97.4% of P. falciparum isolates contained pfcrt K76T mutation, while pfmdr1 N86Y and Y184F mutations were present in 18.2% and 10.2% of the samples. P. vivax pvdhfr S58R mutation was present in 24.9% of isolates and the S117N mutation in 36.2%, while no mutation in the pvdhps gene was found. Pvmdr1 F1076L mutation was found in nearly all samples, as it was observed in 98.9% of isolates. No significant anti-folate and chloroquine resistance was observed in P. vivax; however, mutations associated with antifolate-resistance were found, and the chloroquine-resistant gene has been observed in 100% of P. falciparum isolates. Chloroquine and sulphadoxine-pyrimethamine resistance were found to be high in P. falciparum and low in P. vivax. Chloroquine could still be used for P. vivax infection but need to be tested in vivo, whereas a replacement of the artemisinin combination therapy for P. falciparum appears to be justified

Influence of phytohormones on seed germination of Solanum linnaeanum

The aim of this study was to determine the germination ability and seedling growth of the apple of Sodom by soaking in water, gibberellin (GA3), naphthylacetic acid (NAA), and salicylic acid (SA), separately. The findings showed that NAA at 50 mgL-1 produced superior germination (77.78%), germination speed (1.43 seeds/time interval), hypocotyl length (1.01 cm), hypocotyl diameter (1.13 mm), leaf number (2.66), and root number (17.25), followed by 50 and 100 mgL-1 GA3, particularly in germination percentage. The best root length (5.33 cm) was detected at 100 mgL-1 SA. In contrast, control seeds and water-soaked seeds showed inferior results. The seeds of the apple of Sodom can be germinated successfully as a result of treatment with NAA at 50 mgL-1, followed by GA3 at 50 and 100 mgL-1