Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin

Background

There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).

Methodology/Principal Findings

Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.

Conclusions/Significance

Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.     

In vitro plantlet regeneration of “dwarf” Indian olive (Elaeocarpus robustus Roxb.): a fruit plant of Bangladesh

A plantlet regeneration protocol was developed on pot-grown mature plants of Elaeocarpus robustus Roxb. cv. Dwarf from nodal and leaf explants. The best yield of adventitious shoots was achieved from the leaf-derived calli in a modified MS (MMS₁, half strength of major salts, full strength of minor salts, and vitamins) medium containing 4.0 μM BA + 4.0 μM Kn + 0.5 μM NAA + 15% coconut water (CW). The shoot multiplication rate was amplified about twofold per culture after the addition of 15% CW to the medium. The rate of shoot multiplication reached maximum at the 5th subculture, and it maintained this rate throughout the 3 subsequent subcultures. The best rooting in vitro was investigated by subculturing the microcuttings in an MMS₂ (half strength of both major salts and minor salts and full strength of vitamins) medium containing 1.0 μM IBA in the dark for one initial week at 30°C, followed by subculturing them in a plant-growth regulator (PGR)-free medium in the light. The plantlets raised in vitro were successfully established under ex vitro conditions.     

Obesity,a major risk factor for immunity and severe outcomes of COVID-19

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.     

L'éléphantiasis péno-scrotal. A propos d'un cas

Massive scrotal lymphoedema with gross genital deformation is called penoscrotal elephantiasis. It is a rare syndrome outside of filariasis endemic regions. It is usually idiopathic and rarely congenital or secondary. It is both physically disabling and emotionally distressing for the patient. Surgical treatment is often necessary. The authors report a case of a patient with penoscrotal elephantiasis in whom no aetiology could be found. Complete surgical resection of the diseased tissue and scrotum and penile reconstruction were performed with good cosmetic and functional results.     

A PCR-based method, with internal control, for the detection of Banana bunchy top virus in banana

Banana bunchy top disease is a major constraint to banana production in most regions where this crop is grown. The disease is caused by Banana bunchy top virus (BBTV), a multicomponent, single-stranded DNA virus of the family Nanoviridae. We have designed primers to a conserved region of the master replication-associated protein that are useful for the polymerase chain reaction (PCR)-mediated detection of BBTV. In addition, primers to banana genomic sequence are used as an internal control, overcoming the uncertainty (owing to false-negatives) inherent in PCR diagnostics. Together these primer sets are a valuable tool in the effort to control BBTV, particularly in screening micropropagated banana plantlets for the absence of virus before release to farmers.     

<Emphasis Type="Italic">Streptomyces caldifontis</Emphasis> sp. nov., isolated from a hot water spring of Tatta Pani,Kotli, Pakistan

A Gram-staining positive, non-motile, rod-shaped, catalase positive and oxidase negative bacterium, designated NCCP-1331^T, was isolated from a hot water spring soil collected from Tatta Pani, Kotli, Azad Jammu and Kashmir, Pakistan. The isolate grew at a temperature range of 18-40 °C (optimum 30 °C), pH 6.0–9.0 (optimum 7.0) and with 0–6 % NaCl (optimum 2 % NaCl (w/v)). The phylogenetic analysis based on 16S rRNA gene sequence revealed that strain NCCP-1331^T belonged to the genus Streptomyces and is closely related to Streptomyces brevispora BK160^T with 97.9 % nucleotide similarity, followed by Streptomyces drosdowiczii NRRL B-24297^T with 97.8 % nucleotide similarity. The DNA–DNA relatedness values of strain NCCP-1331^T with S. brevispora KACC 21093^T and S. drosdowiczii CBMAI 0498^T were 42.7 and 34.7 %, respectively. LL-DAP was detected as diagnostic amino acid along with alanine, glycine, leucine and glutamic acid. The isolate contained MK-9(H₈) as the predominant menaquinone. Major polar lipids detected in NCCP-1331^T were phosphatidylethanolamine, phosphatidylinositol and unidentified phospholipids. Major fatty acids were iso-C_{16: 0}, summed feature 8 (18:1 ω7c/18:1 ω6c), anteiso-C_15:0 and C_16:0. The genomic DNA G + C content was 69.8 mol %. On the basis of phylogenetic, phenotypic and chemotaxonomic analysis, it is concluded that strain NCCP-1331^T represents a novel species of the genus Streptomyces, for which the name Streptomyces caldifontis sp. nov. is proposed. The type strain is NCCP-1331^T (=KCTC 39537^T = CPCC 204147^T).     

Scrophularia attariae and S. maharluica spp. nov. (Scrophulariaceae) from south Iran

Two new species of Scrophularia L. sect. Tomiophyllum Benth., S. attariae Ranjbar & Rahchamani and S. maharluica Ranjbar & Rahchamani, are described and illustrated from Fars Province, south Iran. The diagnostic morphological characters of these species and closely related taxa are discussed. The distribution, ecology and conservation status of the new species are also described. The value and utility of stem indumentum and leaf stomata is evaluated as an additional source of information for their taxonomy. Finally, an identification key and distribution map for the new taxa and related species are presented.     

Systematic protein–protein interaction mapping for clinically relevant human GPCRs

G‐protein‐coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR‐mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two‐hybrid (MYTH) approach and identified interacting partners for 48 selected full‐length human ligand‐unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5‐HT4d, and adenosine ADORA2A receptors. Our data represent the first large‐scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins.     

Patient-specific stress analyses in the ascending thoracic aorta using a finite-element implementation of the constrained mixture theory

It is now a rather common approach to perform patient-specific stress analyses of arterial walls using finite-element models reconstructed from gated medical images. However, this requires to compute for every Gauss point the deformation gradient between the current configuration and a stress-free reference configuration. It is technically difficult to define such a reference configuration, and there is actually no guarantee that a stress-free configuration is physically attainable due to the presence of internal stresses in unloaded soft tissues. An alternative framework was proposed by Bellini et al. (Ann Biomed Eng 42(3):488–502, 2014). It consists of computing the deformation gradients between the current configuration and a prestressed reference configuration. We present here the first finite-element results based on this concept using the Abaqus software. The reference configuration is set arbitrarily to the in vivo average geometry of the artery, which is obtained from gated medical images and is assumed to be mechanobiologically homeostatic. For every Gauss point, the stress is split additively into the contributions of each individual load-bearing constituent of the tissue, namely elastin, collagen, smooth muscle cells. Each constituent is assigned an independent prestretch in the reference configuration, named the deposition stretch. The outstanding advantage of the present approach is that it simultaneously computes the in situ stresses existing in the reference configuration and predicts the residual stresses that occur after removing the different loadings applied onto the artery (pressure and axial load). As a proof of concept, we applied it on an ideal thick-wall cylinder and showed that the obtained results were consistent with corresponding experimental and analytical results of the well-known literature. In addition, we developed a patient-specific model of a human ascending thoracic aneurysmal aorta and demonstrated the utility in predicting the wall stress distribution in vivo under the effects of physiological pressure. Finally, we simulated the whole process preceding traditional in vitro uniaxial tensile testing of arteries, including excision from the body, radial cutting, flattening and subsequent tensile loading, showing how this process may impact the final mechanical properties derived from these in vitro tests.