Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes at Osteochondral Interfaces

Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl’s staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd−/−, Hgd tm1a−/−), using Schmorl’s staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation

Subclinical Ochronosis Features In Alkaptonuria: A Cross-Sectional Study

Background Alkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to ochronosis. Age of ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown. Methods In an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI). Results Thirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU. Conclusions Ochronosis can be present before age 20 years

Identifying joint-specific gait mechanisms causing impaired gait in alkaptonuria patients.

BACKGROUND: Alkaptonuria is a rare genetic disease that leads to structural joint damage and impaired movement function. Previous research indicates that alkaptonuria affects gait, however the detailed mechanisms are unknown. RESEARCH QUESTION: What are the joint-specific gait mechanisms which contribute to impaired gait in alkaptonuria patients? METHODS: The gait of 36 alkaptonuria patients were compared to those of 21 unimpaired controls. The AKU patients were split into three age groups (young 16-29 years, n = 9, middle 30-49 years, n = 16 and old 50 + years, n = 11), and the kinematic and kinetic gait profiles were compared to speed-matched controls using a spm1d two-sample t-test. RESULTS: The young AKU group showed significant differences in the sagittal plane of the knee joint compared to speed-matched controls. The middle group showed deviations in the knee and hip joints. The old group showed significant differences in multiple joints and planes and exhibited gait mechanisms which may be compensation strategies. SIGNIFICANCE: This study is the first to identify and describe joint-specific mechanisms during gait in alkaptonuria patients. Gait deviations were evident even in young AKU patients, including a 16-year-old, much earlier than previously thought. The knee joint is an important focus of future research and potential interventions as deviations were found across all three AKU age groups

Intrinsic connectivity reveals functionally distinct cortico-hippocampal networks in the human brain

Episodic memory depends on interactions between the hippocampus and interconnected neocortical regions. Here, using data-driven analyses of resting-state functional magnetic resonance imaging (fMRI) data, we identified the networks that interact with the hippocampus-the default mode network (DMN) and a "medial temporal network" (MTN) that included regions in the medial temporal lobe (MTL) and precuneus. We observed that the MTN plays a critical role in connecting the visual network to the DMN and hippocampus. The DMN could be further divided into 3 subnetworks: a "posterior medial" (PM) subnetwork comprised of posterior cingulate and lateral parietal cortices; an "anterior temporal" (AT) subnetwork comprised of regions in the temporopolar and dorsomedial prefrontal cortex; and a "medial prefrontal" (MP) subnetwork comprised of regions primarily in the medial prefrontal cortex (mPFC). These networks vary in their functional connectivity (FC) along the hippocampal long axis and represent different kinds of information during memory-guided decision-making. Finally, a Neurosynth meta-analysis of fMRI studies suggests new hypotheses regarding the functions of the MTN and DMN subnetworks, providing a framework to guide future research on the neural architecture of episodic memory

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Not AvailableAn experiment was carried out to evaluate the efficacy o newer molecules in the management of Tuta absoluta an invasive pest in tomato. The insecticide viz., cyazypyr @ 1.8nml/L. rynaxypyr @ 0.3 ml/L and indoxocarb @ 1ml/L were the effective treatments.Not Availabl

Asymmetric cell division--how flowering plant cells get their unique identity.

A central question in biology is how cell fate is specified during development of a multicellular organism. Flowering plants use two major pathways of asymmetric cell divisions in a spatio-temporal manner to achieve required cellular differentiation. In the 'one mother--two different daughters' pathway, a mother cell mitotically divides to produce two daughter cells of different size and fate. By contrast, the 'coenocyte-cellularization' pathway involves formation of a coenocyte, nuclear migration to specific locations of the coenocyte and cellularization of these nuclei by unique wall forming processes. Given that cell fate determinants play a key role in establishing cell identity, their allocation to daughter cells in the two pathways needs to be understood in terms of the unique cell cycle regulatory mechanisms involved. Most of the information available on cell fate determination in flowering plants is in the form of genes identified from mutant analysis. Novel techniques of interrogating individual plant cells in vivo are necessary to advance the extant knowledge from genetics to functional genomics data bases