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Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG 1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro . They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca 2+ uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca 2+ -induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca 2+ -induced membrane depolarisation and Ca 2+ retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature.

An insight into a previously unknown step in B 12 biosynthesis was unexpectedly obtained through our analysis of a mutant of the symbiotic nitrogen fixing bacterium Sinorhizobium meliloti . This mutant was identified based on its unusually bright fluorescence on plates containing the succinoglycan binding dye calcofluor. The mutant contains a Tn 5 insertion in a gene that has not been characterized previously in S. meliloti . The closest known homolog is the bluB gene of Rhodobacter capsulatus , which is implicated in the biosynthesis of B 12 (cobalamin). The S. meliloti bluB mutant is unable to grow in minimal media and fails to establish a symbiosis with alfalfa, and these defects can be rescued by the addition of vitamin B 12 (cyanocobalamin) or the lower ligand of cobalamin, 5,6-dimethylbenzimidazole (DMB). Biochemical analysis demonstrated that the bluB mutant does not produce cobalamin unless DMB is supplied. Sequence comparison suggests that BluB is a member of the NADH/flavin mononucleotide (FMN)-dependent nitroreductase family, and we propose that it is involved in the conversion of FMN to DMB. cobalamin symbiosis bacteria vitamin B12 biosynthesis

BackgroundSolitary kidney may be congenital or as a result of nephrectomy. There is a lot of literature available on quality of life in these patients, but there is limited data on pregnancy outcome.ObjectivesTo study pregnancy outcome in patients with solitary kidney either congenital or due to nephrectomy.Materials and MethodsStudy Design This is a retrospective observational study conducted at tertiary health center in Ahmedabad, from 2011 to 2014. Sample Size There were 164 patients of solitary kidney, out of which two patients had congenital solitary kidney and the remaining had solitary kidney due to nephrectomy. Among 164 patients, 96 (58.53 %) patients had completed family, 37 (22.56 %) patients did not try for pregnancy, 15 (9.14 %) patients have conceived, 12 (7.3 %) were lost to follow up and 4 (2.43 %) patients were infertile. Method Patients in reproductive age group (20–40 years), with solitary kidney either congenital or due to nephrectomy, were included. Maternal and fetal outcome was studied, and patients were followed up till 2 years postpartum. Exclusion Criteria Patients with solitary kidney due to post-renal transplant were excluded.ResultsThere were 15 (9.14 %) patients who had conceived, out of which 11 (73.33) patients delivered and 4 (26.67 %) patients had spontaneous abortion. Two patients developed gestational hypertension and one had preeclampsia. On follow-up, all babies were normal and none of them had delayed developmental milestones.ConclusionPreconceptional counseling should be done in these patients regarding risk of developing preeclampsia during pregnancy and preterm delivery. These patients can have good pregnancy outcome with close monitoring during antenatal period.

It was reported that some proteins known to cause renal cystic disease (NPHP6; BBS1, and BBS4) also localize to the olfactory epithelium (OE), and that mutations in these proteins can cause anosmia in addition to renal cystic disease. We demonstrate here that a number of other proteins associated with renal cystic diseases - polycystin 1 and 2 (PC1, PC2), and Meckel-Gruber syndrome 1 and 3 (MKS1, MKS3) - localize to the murine OE. PC1, PC2, MKS1 and MKS3 are all detected in the OE by RT-PCR. We find that MKS3 localizes specifically to dendritic knobs of olfactory sensory neurons (OSNs), while PC1 localizes to both dendritic knobs and cilia of mature OSNs. In mice carrying mutations in MKS1, the expression of the olfactory adenylate cyclase (AC3) is substantially reduced. Moreover, in rats with renal cystic disease caused by a mutation in MKS3, the laminar organization of the OE is perturbed and there is a reduced expression of components of the odor transduction cascade (G(olf), AC3) and α-acetylated tubulin. Furthermore, we show with electron microscopy that cilia in MKS3 mutant animals do not manifest the proper microtubule architecture. Both MKS1 and MKS3 mutant animals show no obvious alterations in odor receptor expression. These data show that multiple renal cystic proteins localize to the OE, where we speculate that they work together to regulate aspects of the development, maintenance or physiological activities of cilia.

An insight into a previously unknown step in B 12 biosynthesis was unexpectedly obtained through our analysis of a mutant of the symbiotic nitrogen fixing bacterium Sinorhizobium meliloti . This mutant was identified based on its unusually bright fluorescence on plates containing the succinoglycan binding dye calcofluor. The mutant contains a Tn 5 insertion in a gene that has not been characterized previously in S. meliloti . The closest known homolog is the bluB gene of Rhodobacter capsulatus , which is implicated in the biosynthesis of B 12 (cobalamin). The S. meliloti bluB mutant is unable to grow in minimal media and fails to establish a symbiosis with alfalfa, and these defects can be rescued by the addition of vitamin B 12 (cyanocobalamin) or the lower ligand of cobalamin, 5,6-dimethylbenzimidazole (DMB). Biochemical analysis demonstrated that the bluB mutant does not produce cobalamin unless DMB is supplied. Sequence comparison suggests that BluB is a member of the NADH/flavin mononucleotide (FMN)-dependent nitroreductase family, and we propose that it is involved in the conversion of FMN to DMB.

BackgroundThe number of patients undergoing renal transplant are increasing with time. Most of these patients fall in the reproductive age group, who are going to conceive sooner or later. But there are few recipients who either are infertile before transplant or became infertile due to underlying renal pathology responsible for transplantation.ObjectiveTo study fertility outcome in female renal transplant recipients.Materials and MethodsStudy design: This is a retrospective study conducted at tertiary health center in Ahmedabad, from 2004 to 2014. Inclusion criteria: Renal transplant recipients in the reproductive age group (20–40 years of age) were followed up in gynecology outdoor patient department. Sample size: There were 211 female renal transplant recipients, out of which 113 (53.5 %) patients had complete family, 3 (1.41 %) patients were infertile, 16 (7.58 %) patients have conceived, 33 (15.63 %) patients were lost to follow-up and remaining 46 (21.8 %) did not try for pregnancy. Exclusion criteria: Unmarried patients, divorced and widow patients were excluded.ResultsOut of 19 patients, 16 patients conceived and 3 were infertile. The main cause of infertility in these patients was ovarian factor in 2 patients and tubal factor in 1 patient. Among 16 patients, 8 patients had missed abortion, 2 patients had preterm deliveries and 6 patients had term deliveries.ConclusionPeritransplant and preconceptional counseling plays an important role for renal transplant recipients to help them understand the effect of renal pathology and transplantation on their fertility. They can have good fertility and pregnancy outcome with optimum functioning graft.

Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common finding on histopathology among patients with ICI-associated acute kidney injury (ICI-AKI). Patients with ICI-AIN often have T cell-dominant infiltration of the kidney and high tissue levels of CXCR3 ligands like CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood. We applied a sub-cellular spatial transcriptomics platform (Xenium Prime 5K) to compare the cellular composition of kidney biopsy tissue from patients with ICI-AIN with ICI-treated patients with acute tubular necrosis (ICI-ATN). Across 8 kidney biopsy specimens (4 with ICI-AIN, 4 with ICI-ATN), we analyzed 332,000 cells, comprising kidney parenchymal cells and infiltrating immune cells. Using a spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to unique fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-γ)/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8 T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8 T cell-derived IFN-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. Spatial transcriptomics reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN. IFN-γ-producing CD8 T cells are likely key drivers of ICI-AIN and should be investigated as future therapeutic targets.

An insight into a previously unknown step in$B_{12}$biosynthesis was unexpectedly obtained through our analysis of a mutant of the symbiotic nitrogen fixing bacterium Sinorhizobium meliloti. This mutant was identified based on its unusually bright fluorescence on plates containing the succinoglycan binding dye calcofluor. The mutant contains a Tn5 insertion in a gene that has not been characterized previously in S. meliloti. The closest known homolog is the bluB gene of Rhodobacter capsulatus, which is implicated in the biosynthesis of$B_{12}$(cobalamin). The S. meliloti bluB mutant is unable to grow in minimal media and fails to establish a symbiosis with alfalfa, and these defects can be rescued by the addition of vitamin$B_{12}$(cyanocobalamin) or the lower ligand of cobalamin, 5,6-dimethylbenzimidazole (DMB). Biochemical analysis demonstrated that the bluB mutant does not produce cobalamin unless DMB is supplied. Sequence comparison suggests that BluB is a member of the NADH/flavin mononucleotide (FMN)-dependent nitroreductase family, and we propose that it is involved in the conversion of FMN to DMB.

An insight into a previously unknown step in B sub(12) biosynthesis was unexpectedly obtained through our analysis of a mutant of the symbiotic nitrogen fixing bacterium Sinorhizobium meliloti. This mutant was identified based on its unusually bright fluorescence on plates containing the succinoglycan binding dye calcofluor. The mutant contains a Tn5 insertion in a gene that has not been characterized previously in S. meliloti. The closest known homolog is the bluB gene of Rhodobacter capsulatus, which is implicated in the biosynthesis of B sub(12) (cobalamin). The S. meliloti bluB mutant is unable to grow in minimal media and fails to establish a symbiosis with alfalfa, and these defects can be rescued by the addition of vitamin B sub(12) (cyanocobalamin) or the lower ligand of cobalamin, 5,6-dimethylbenzimidazole (DMB). Biochemical analysis demonstrated that the bluB mutant does not produce cobalamin unless DMB is supplied. Sequence comparison suggests that BluB is a member of the NADH/flavin mononucleotide (FMN)-dependent nitroreductase family, and we propose that it is involved in the conversion of FMN to DMB.