Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling

De novo mutations in CHD8 are strongly associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural-specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of Chd8 expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the neurodevelopmental role of Chd8.National Institutes of Health (U.S.) (Grant UH1-MH106018-03

The classification of glomerulonephritis in systemic lupus erythematosus revisited

The classification of glomerulonephritis in systemic lupus erythematosus revisited.The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involvin

Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7–9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease

Anti-neutrophil cytoplasmic antibodies:Current diagnostic and pathophysiological potential

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by rapid deterioration of renal function occurring within days or weeks together with signs of glomerulonephritis, that is, proteinuria and hematuria with cellular casts. The syndrome is, in many cases, histopathologically manifested as fibrinoid necrosis of the capillary wall with extracapillary proliferation and crescent formation [1]. This so-called necrotizing crescentic glomerulonephritis (NCGN) is seen in 5 to 15% of renal biopsies in most series [1–3]. Although it is infrequent, the importance of the condition is illustrated by the fact that most cases of NCGN, if left untreated, develop renal failure within days or weeks [1]. Based on immunohistopathology NCGN can be subdivided into three distinct categories. The first one, occurring in 2 to 20% of the cases and characterized by linear staining of the glomerular capillary wall for immunoglobulin and complement, has classically been described as anti-glomerular basement membrane (GBM) disease. It is associated with autoantibodies to structural antigens of the GBM, in particular to the first globular noncollagen domain of collagen type IV [4]. The antibodies are considered of pathogenetic significance. The second category, comprising 15 to 50% of cases, is characterized by granular deposits of immunoglobulin and complement suggesting that immune complexes are pathogenetically involved. This type occurs in conjunction with systemic autoimmune diseases such as lupus erythematosus, in cases of post-infectious glomerulonephritis, IgA nephropathy or Henoch-Schönlein purpura, or as an idiopathic variety. The third group of NCGN, occurring in 40 to 80%, demonstrates only a few or no immune deposits and is designated as pauci-immune NCGN [1–3, 5, 6]. Pauci-immune NCGN occurs as part of Wegener's granulomatosis (WG) or related conditions, or without systemic vasculitis (idiopathic NCGN). The pathophysiology of this pauci-immune type of NCGN has not been elucidated. Within the last decade, however, it has been recognized that the condition is associated with autoantibodies to cytoplasmic components of neutrophils (anti-neutrophil cytoplasmic antibodies or ANCA).ANCA were first described in 1982 by Davies et al in a few patients with segmental necrotizing glomerulonephritis [7]. Only in 1985 did it become apparent that ANCA are a sensitive and specific marker for Wegener's granulomatosis (WG) [8]. Later on, ANCA were described in patients with microscopic polyarteritis [9]. Falk and Jennette, in 1988, showed that ANCA are also associated with the idiopathic form of pauci-immune NCGN [10]. These data have now been confirmed by many groups and support the view that ANCA-associated glomerulonephritis and vasculitis is, indeed, a distinct disease category. A number of studies, in addition, have suggested that ANCA are involved in the pathophysiology of the aforementioned disorders. As ANCA, however, have recently also been detected in a wide range of inflammatory and infectious conditions, a critical reappraisal of the diagnostic significance of ANCA-testing seems justified.In this review we will evaluate the current state of ANCA-testing as well as elaborate on the pathophysiological role of the autoantibodies in necrotizing glomerulonephritis and vasculitis. Data presented recently at the Fifth International Workshop on ANCA, held in Cambridge, United Kingdom, will be included [11]. As such, it adds to previous reviews on ANCA that were published following the Second [12], Third [13], and Fourth [14] Workshops on ANCA

Tigers of Sundarbans in India: Is the Population a Separate Conservation Unit?

The Sundarbans tiger inhabits a unique mangrove habitat and are morphologically distinct from the recognized tiger subspecies in terms of skull morphometrics and body size. Thus, there is an urgent need to assess their ecological and genetic distinctiveness and determine if Sundarbans tigers should be defined and managed as separate conservation unit. We utilized nine microsatellites and 3 kb from four mitochondrial DNA (mtDNA) genes to estimate genetic variability, population structure, demographic parameters and visualize historic and contemporary connectivity among tiger populations from Sundarbans and mainland India. We also evaluated the traits that determine exchangeability or adaptive differences among tiger populations. Data from both markers suggest that Sundarbans tiger is not a separate tiger subspecies and should be regarded as Bengal tiger (P. t. tigris) subspecies. Maximum likelihood phylogenetic analyses of the mtDNA data revealed reciprocal monophyly. Genetic differentiation was found stronger for mtDNA than nuclear DNA. Microsatellite markers indicated low genetic variation in Sundarbans tigers (He= 0.58) as compared to other mainland populations, such as northern and Peninsular (Hebetween 0.67- 0.70). Molecular data supports migration between mainland and Sundarbans populations until very recent times. We attribute this reduction in gene flow to accelerated fragmentation and habitat alteration in the landscape over the past few centuries. Demographic analyses suggest that Sundarbans tigers have diverged recently from peninsular tiger population within last 2000 years. Sundarbans tigers are the most divergent group of Bengal tigers, and ecologically non-exchangeable with other tiger populations, and thus should be managed as a separate "evolutionarily significant unit" (ESU) following the adaptive evolutionary conservation (AEC) concept.Wildlife Institute of India, Dehra Dun (India)

Increased care at discharge from COVID-19: The association between pre-admission frailty and increased care needs after hospital discharge; a multicentre European observational cohort study

Background: The COVID-19 pandemic has placed significant pressure on health and social care. Survivors of COVID-19 may be left with substantial functional deficits requiring ongoing care. We aimed to determine whether pre-admission frailty was associated with increased care needs at discharge for patients admitted to hospital with COVID-19. Methods: Patients were included if aged over 18 years old and admitted to hospital with COVID-19 between 27 February and 10 June 2020. The Clinical Frailty Scale (CFS) was used to assess pre-admission frailty status. Admission and discharge care levels were recorded. Data were analysed using a mixed-effects logistic regression adjusted for age, sex, smoking status, comorbidities, and admission CRP as a marker of severity of disease. Results: Thirteen hospitals included patients: 1671 patients were screened, and 840 were excluded including, 521 patients who died before discharge (31.1%). Of the 831 patients who were discharged, the median age was 71 years (IQR, 58–81 years) and 369 (44.4%) were women. The median length of hospital stay was 12 days (IQR 6–24). Using the CFS, 438 (47.0%) were living with frailty (≥ CFS 5), and 193 (23.2%) required an increase in the level of care provided. Multivariable analysis showed that frailty was associated with an increase in care needs compared to patients without frailty (CFS 1–3). The adjusted odds ratios (aOR) were as follows: CFS 4, 1.99 (0.97–4.11); CFS 5, 3.77 (1.94–7.32); CFS 6, 4.04 (2.09–7.82); CFS 7, 2.16 (1.12–4.20); and CFS 8, 3.19 (1.06–9.56). Conclusions: Around a quarter of patients admitted with COVID-19 had increased care needs at discharge. Pre-admission frailty was strongly associated with the need for an increased level of care at discharge. Our results have implications for service planning and public health policy as well as a person's functional outcome, suggesting that frailty screening should be utilised for predictive modelling and early individualised discharge planning

De novoCIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases

Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome