Glycan deletions in the HIV-1 gp120 V1/V2 domain compromise viral infectivity, sensitize the mutant virus strains to carbohydrate-binding agents and represent a specific target for therapeutic intervention

AbstractCarbohydrate-binding agents (CBAs), such as the mannose-specific Hippeastrum hybrid agglutinin (HHA) and the GlcNAc-specific Urtica dioica agglutinin (UDA), frequently select for glycan deletions in all different domains of HIV-1 gp120, except in the V1/V2 domain. To reveal the underlying mechanisms, a broad variety of 31 different virus strains containing one or several N-glycan deletions in V1/V2 of the gp120 of the X4-tropic HIV-1NL4.3 were constructed by chimeric virus technology. No co-receptor switch to CCR5 was observed for any of the replication-competent mutant virus strains. With a few exceptions, the more glycans were deleted in the gp120 V1/V2 domain, the more the replication capacity of the mutant viruses became compromised. None of the mutant virus strains showed a markedly decreased sensitivity to the inhibitory activity of HHA and UDA. Instead, an up to 2- to 10-fold higher sensitivity to the inhibitory activity of these CBAs was observed. Our data may provide an explanation why glycan deletions in the gp120 V1/V2 domain rarely occur under CBA pressure and confirm the important functional role of the glycans in the HIV-1 gp120 V1/V2 domain. The gp120 V1/V2 loop glycans of HIV-1 should therefore be considered as a hot spot and novel target for specific therapeutic drug intervention

HIV-1 protease mutation 82M contributes to phenotypic resistance to protease inhibitors in subtype G

Objectives The purpose of this study was the qualitative and quantitative assessment of the in vitro effect of HIV-1 protease (PR) mutation 82M on replication capacity and susceptibility to the eight clinically available PR inhibitors (PIs). Methods The 82M substitution was introduced by site-directed mutagenesis in wild-type subtype B and G strains, as well as reverted back to wild-type in a therapy-failing strain. The recombinant viruses were evaluated for their replication capacity and susceptibility to PIs. Results The single 82M mutation within a wild-type subtype B or G background did not result in drug resistance. However, the in vitro effect of single PR mutations on PI susceptibility is not always distinguishable from wild-type virus, and particular background mutations and polymorphisms are required to detect significant differences in the drug susceptibility profile. Consequently, reverting the 82M mutation back to wild-type (82I) in a subtype G isolate from a patient that failed therapy with multiple other PR mutations did result in significant increases in susceptibility towards indinavir and lopinavir and minor increases in susceptibility towards amprenavir and atazanavir. The presence of the 82M mutation also slightly decreased viral replication, whether it was in the genetic background of subtype B or subtype G. Conclusions Our results suggest that 82M has an impact on PI susceptibility and that this effect is not due to a compensatory effect on the replication capacity. Because 82M is not observed as a polymorphism in any subtype, these observations support the inclusion of 82M in drug resistance interpretation systems and PI mutation list

Praktik Utang Piutang dalam Perspektif Ekonomi Islam di Kecamatan Binuang Kabupaten Polewali Mandar

Hasil penelitian ini menunjukkan bahwa dalam praktik utang piutang di Kecamatan Binuang Kabupaten Polewali Mandar dilihat dari sisi pola utang piutang yang di mana utang piutang berdasarkan jaminan tidak sesuai dengan hukum syar'i dan pola utang piutang tanpa jaminan sesuai dengan hukum syar'i. Adapun faktor pendorong masyarakat melakukan utang piutang yaitu karena adanya faktor kemudahan, kebutuhan, ekonomi, dan pendidikan

Extremity ring dosimetry intercomparison in reference and workplace fields

An intercomparison of ring dosemeters has been organised with the aim of assessing the technical capabilities of available extremity dosemeters and focusing on their performance at clinical workplaces with potentially high extremity doses. Twenty-four services from 16 countries participated in the intercomparison. The dosemeters were exposed to reference photon (137Cs) and beta (147Pm, 85Kr and 90Sr/90Y) fields together with fields representing realistic exposure situations in interventional radiology (direct and scattered radiation) and nuclear medicine (99 mTc and 18F). It has been found that most dosemeters provided satisfactory measurements of Hp(0.07) for photon radiation, both in reference and realistic fields. However, only four dosemeters fulfilled the established requirements for all radiation qualities. The main difficulties were found for the measurement of low-energy beta radiation. Finally, the results also showed a general under-response of detectors to 18F, which was attributed to the difficulties of the dosimetric systems to measure the positron contribution to the dos

Epidemiological profile and clinico-pathological features of pediatric gynecological cancers at Moi Teaching & Referral Hospital, Kenya

Background: The main pediatric (0–18 years) gynecologic cancers include stromal carcinomas (juvenile granulosa cell tumors and Sertoli-Leydig cell tumors), genital rhabdomyosarcomas and ovarian germ cell. Outcomes depend on time of diagnosis, stage, tumor type and treatment which can have long-term effects on the reproductive career of these patients. This study seeks to analyze the trends in clinical-pathologic presentation, treatment and outcomes in the cases seen at our facility. This is the first paper identifying these cancers published from sub-Saharan Africa. Method: Retrospective review of clinico-pathologic profiles and treatment outcomes of pediatric gynecologic oncology patients managed at MTRH between 2010 and 2020. Data was abstracted from gynecologic oncology database and medical charts. Results: Records of 40 patients were analyzed. Most, (92.5%, 37/40) of the patients were between 10 and 18 years. Ovarian germ cell tumors were the leading histological diagnosis in 72.5% (29/40) of the patients; with dysgerminomas being the commonest subtype seen in 12 of the 37 patients (32.4%). The patients received platinum-based chemotherapy in 70% of cases (28/40). There were 14 deaths among the 40 patients (35%) Conclusion: Surgery remains the main stay of treatment and fertility-sparing surgery with or without adjuvant platinum-based chemotherapy are the standard of care with excellent prognosis following early detection and treatment initiation. LMICs face several challenges in access to quality care and that affects survival of these patients. Due to its commonality, ovarian germ cell cancers warrant a high index of suspicion amongst primary care providers attending to adnexal masses in this age group