Organo-functionalized metal–oxide clusters: synthesis and characterization of the reduced cationic species [NaV IV 6 O 6 {(OCH 2 CH 2 ) 2 NH} 6 ] +

A new heteropolyoxovanadium compound, [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O), was synthesized and characterized by single-crystal X-ray diffraction analysis, cyclic voltammetry, FTIR and UV-vis spectroscopy, and TGA. [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O) contains the diethanolamine functionalized oxovanadium cationic cluster, [NaV(IV)6O6{(OCH2CH2)2NH}6](+). The cluster cation is composed of a fully reduced cyclic {NaV6N6O18} framework which adopts an Anderson-like structure and is comprised of a ring of six edge-sharing {VO5N} octahedra linked to a central {NaO6} unit. Two (OCH2CH2-) arms of each of the six diethanolamine ligands are incorporated into the oxometalate core. FTIR spectra are consistent with the presence of expected V=Ot stretching modes and functionalization with diethanolamine. Electrochemical and UV-vis absorption properties are consistent with two distinct MLCT processes: the characteristic V=Ot dπ-pπ interaction, and a second process occurring through the hydrogen-terminated nitrogen atoms (V-N-H) of the octahedra forming the cyclic {NaV6N6O18} core

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy

Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We now show that glutamine and glucose also fuel an indispensible dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of UDP-GlcNAc, a substrate for cellular glycosyltransferases. Immune activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-GlcNAc glycosyltransferase as compared to naïve cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation, via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation, and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology

Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.

Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression

Wits Transplant Unit Annual Report 2022: Adult and paediatric liver transplantation

In 2022, the Wits Transplant Unit performed 57 liver transplants: 33/57 adult (58%) and 24/57 paediatric (42%) recipients. At the beginning of 2022, 28 candidates were on the adult waitlist. Forty-six candidates were added to the waitlist during the year. Sixty-five percent of waitlisted candidate were transplanted. Adult candidates remained on the waitlist for longer than previous years, with 52% of them waitlisted for less than one year before undergoing liver transplantation. There was a decrease in adult pretransplant mortality to 9% in 2021 from 25% in 2020. The most common aetiology in waitlist candidates was alcoholic steatohepatitis (ASH)/non-alcoholic steatohepatitis (NASH) (36%) and in recipients cholestatic (primary sclerosing cholangitis (PSC) and primary biliary sclerosis (PBC)) (40%). Most adult recipients received a deceased donor graft (79%). Unadjusted recipient one- and three-year survivals were 75% (95% confidence interval (CI) 65 - 83) and 74% (95% CI 65 - 81), respectively. In the paediatric population, the most common aetiologies for both pretransplant candidates and transplant recipients remained cholestatic disease and acute liver failure. There was a decrease in paediatric pretransplant mortality from 27% in 2017 to 6% in 2021. Unlike the adult cohort, most paediatric recipients received a living donor graft (79%). Unadjusted one-year and three-year survival rates were 85% (95% CI 75 - 92) and 68% (95% CI 56 - 77), respectively.

The paediatric liver transplant experience in Johannesburg, South Africa: A broad overview and update

Background: The Wits Transplant Unit performed its first paediatric liver transplant in 2005. Initial experiences from the unit were published in 2012 and 2014. Since then, significant progress has been made in capacity-building the unit, improving outcomes and enhancing service delivery. This paper presents a broad overview and update of the unit’s 17-year experience.   Methods: We conducted a retrospective review of all paediatric liver transplants performed in Johannesburg from 1 January 2005 to 31 December 2021 with a minimum one-year follow-up. Data were accessed from the Wits Donald Gordon Medical Centre Paediatric Liver Transplant Research Database (University of the Witwatersrand Human Research Ethics approval: M190749). The following data were collected: donor and recipient sociodemographic and clinical characteristics, details of transplant procedures, donor grafts and recipient outcomes (post-operative complications, graft and recipient survival).   Results: A total of 270 transplants were performed during the review period. Two thirds of recipients (n=180, 67%) were younger than 5 years at time of transplant and half (n=135, 50%) received a living donor graft. The most common indication for liver transplant was biliary atresia, followed by acute liver failure. Unadjusted recipient survival was 80% (95% CI: 75-85%) at one year, and 68% (95% CI: 59-75%) at five years. Waiting list mortality decreased from 27.3% in 2017 to 5.9% in 2021. One hundred and fifty-four (57.0%) recipients experienced at least one type of intervention requiring surgical complication - the most common being biliary in nature (n = 91; 33.7%).   Conclusion: Over last seventeen years, a sustainable paediatric liver transplantation service has been established in Johannesburg. Living donor, split and ABO incompatible liver transplants have been incorporated in response to the severe organ shortage in South Africa. However, our outcomes can be improved. Additionally, a national transplant initiative to coordinate timeous referrals and expand access to liver transplantation for children with severe acute and chronic liver failure is advised

COPI Is Required for Enterovirus 71 Replication

Enterovirus 71 (EV71), a member of the Picornaviridae family, is found in Asian countries where it causes a wide range of human diseases. No effective therapy is available for the treatment of these infections. Picornaviruses undergo RNA replication in association with membranes of infected cells. COPI and COPII have been shown to be involved in the formation of picornavirus-induced vesicles. Replication of several picornaviruses, including poliovirus and Echovirus 11 (EV11), is dependent on COPI or COPII. Here, we report that COPI, but not COPII, is required for EV71 replication. Replication of EV71 was inhibited by brefeldin A and golgicide A, inhibitors of COPI activity. Furthermore, we found EV71 2C protein interacted with COPI subunits by co-immunoprecipitation and GST pull-down assay, indicating that COPI coatomer might be directed to the viral replication complex through viral 2C protein. Additionally, because the pathway is conserved among different species of enteroviruses, it may represent a novel target for antiviral therapies

Cisplatin-induced ototoxicity: the current state of ototoxicity monitoring in New Zealand.

Background: Many well-known pharmacologic agents have been shown to have toxic effects to the cochleo-vestibular system. Examples of such ototoxic agents include cisplatin and aminoglycoside antibiotics. Ototoxicity monitoring consists of a comprehensive pattern of audiological assessments designed to detect the onset of any hearing loss. Three main methods have emerged over the past decade, and include the basic audiological assessment, extended high frequency (EHF) audiometry, and otoacoustic emission (OAE) measurement. These measures can be used separately or in combination, depending on clinical purpose and patient considerations. It is suggested by the American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring, that baseline testing be done in a fairly comprehensive manner, including pure-tone thresholds in both the conventional- and extended high frequency ranges, tympanometry, speech audiometry, and the testing of OAEs (AAA, 2009). Anecdotal evidence suggests that New Zealand Audiologists do not currently follow a national ototoxicity monitoring protocol. Therefore the main aim of this study was to explore the current status of ototoxicity monitoring within New Zealand. Hypothesis: It was hypothesized that hospital based Audiology departments across New Zealand each followed their own internal ototoxicity monitoring protocol based, to a large extent, on the guidelines proposed by the American Academy of Audiology and by the American Speech-Language-Hearing Association. Method: Through the use of a Telephone Interview Questionnaire, 16 charge Audiologists were interviewed to establish their current state of knowledge regarding ototoxicity monitoring at 16 out of 20 district health boards in New Zealand. Enquiries about the current systems and procedures in place at their departments together with any suggestions and recommendations to improve on these systems were made. Results: This study found that only 9 of the 16 DHBs interviewed currently follow an ototoxicity monitoring protocol. Furthermore, other than initially hypothesized the origin of the protocols followed by the remaining 7 departments were reported to have ranged from independently developed protocols to historically adopted protocols. One department implemented an adapted version of a protocol by Fausti et al. (Ear and Hearing 1999; 20(6):497-505). This diversity in origin however, does confirm our initial suspicion that no universal and standardized monitoring protocol is currently being followed by Audiologists working in the public health sector of New Zealand

Unlike for Human Monocytes after LPS Activation, Release of TNF-α by THP-1 Cells Is Produced by a TACE Catalytically Different from Constitutive TACE

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-α, initially synthesized as a membrane-anchored precursor (pro-TNF-α), is processed by proteolytic cleavage to generate the secreted mature form. TNF-α converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-α.Here, we demonstrated the presence on THP-1 cells as on human monocytes of a constitutive proteolytical activity able to cleave pro-TNF-α. Revelation of the cell surface TACE protein expression confirmed that the observed catalytic activity is due to TACE. However, further studies using effective and innovative TNF-α inhibitors, as well as a highly selective TACE inhibitor, support the presence of a catalytically different sheddase activity on LPS activated THP-1 cells. It appears that this catalytically different TACE protease activity might have a significant contribution to TNF-α release in LPS activated THP-1 cells, by contrast to human monocytes where the TACE activity remains catalytically unchanged even after LPS activation.On the surface of LPS activated THP-1 cells we identified a releasing TNF-α activity, catalytically different from the sheddase activity observed on human monocytes from healthy donors. This catalytically-modified TACE activity is different from the constitutive shedding activity and appears only upon stimulation by LPS