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Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1–4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin–IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.

Objective Pyogenic spondylodiscitis is a severe medical condition, often requiring surgical intervention. Numerous risk factors are known, such as obesity, neurological impairment and old age. In-hospital mortality remains high, therefore other factors may be contributing to the increased mortality. To evaluate kidney function as a risk factor for increased morbidity of pyogenic spondylodiscitis, the glomerular filtration rate (GFR) was correlated with the patients' clinical course. Materials and methods We retrospectively reviewed the cases of 366 patients and 255 were included for analysis. Clinical, laboratory and surgical data were recorded with a minimum follow-up of three months. For clinical outcome measurement, mortality, length of stay and perioperative complications were analysed. Results The study included 255 patients (173 men, 82 women; mean age 66.3 years). Patients with a GFR p = 0.071). The mortality rate increased significantly with a decrease in GFR: A GFR of 30–59 mL/min had a mortality rate of 17.6%, whereas a GFR of p = 0.003). Patients with impaired GFR showed an increased rate of postoperative complications (OR 4.7 p = 0.002) and higher rate of intensive care unit (ICU) stay (OR 8.7 p = Discussion Preoperative GFR values showed a significant correlation with in-hospital mortality in patients with spondylodiscitis, when graded according to the KDIGO stages. Furthermore, a GFR of

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients’ previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 ($$p p < 0.001) and 6 months ($$p p < 0.001). Relapse-free survival increased from 4.5 months (95%-CI 3–10 months) to 21 months (95%-CI 16–32 months) ($$p p < 0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.

The Comprehensive Geriatric Assessment (CGA) provides essential information about older hospitalized patients but is either not systematically adopted or not adopted at all in clinical routine. As a consequence, critical factors influencing patients' trajectories, like personal resources (geriatric resources, GR), geriatric syndromes (GS), health-related quality of life (HRQoL) and multidimensional prognosis often escape routine diagnostics.To investigate the association between HRQoL and GR/GS as well as its prognostic signature.In this study 165 inpatients older than 65 years admitted to an internal medicine department of a German large metropolitan hospital were assessed by a CGA-based calculation of the multidimensional prognostic index (MPI). Ten different GR and 17 GS, as well as HRQoL were collected. After 3, 6 and 12 months the patients were followed-up by telephone.The HRQoL was associated with MPI (p 0.001), number of GS (p 0.001) and survival days after discharge (p = 0.008). Additionally, significant associations were found between HRQoL and number of GR (p 0.001). GS displaying risk for physical dependence like instability (p 0.001) and chronic pain (p = 0.007) and single GR/GS that influence patient's confidence like isolation (p 0.001), depression (p 0.001) and emotional resources (p = 0.002) were also associated with HRQoL.The HRQoL is significantly associated to specific risk and protective factor profiles of GR and GS. To improve quality of life, targeted, patient-centered diagnostics and treatment of GS as well as stabilization of GR should be encouraged in the management of older, multimorbid patients outside geriatric settings.HINTERGRUND: Das multidimensionale Assessment (Comprehensive Geriatric Assessment, CGA) liefert entscheidende Informationen über hospitalisierte ältere Patienten, wird aber in nichtgeriatrischen Versorgungsstrukturen nicht konsequent angewendet. Als Folge werden kritische Faktoren für Patientenverläufe häufig nicht adressiert, wie persönliche Ressourcen, geriatrische Syndrome (GS), Lebensqualität und die multidimensionale Prognose.Untersuchung der Assoziation zwischen gesundheitsbezogener Lebensqualität („health-related quality of life, HRQoL“), GS und Ressourcen (GR) sowie multidimensionaler Prognose.Bei 165 über 65-jährigen hospitalisierten Patienten unter Hochleistungsmedizin wurden der CGA-basierter multidimensionaler prognostischer Index (MPI), 10 GR, 17 GS sowie die HRQoL erhoben. Follow-up-Anrufe wurden 3, 6 und 12 Monate nach Entlassung durchgeführt.Die HRQoL war mit dem MPI (p 0,001), der Anzahl der GS (p 0,001) und der Überlebenszeit nach Entlassung (p = 0,008) assoziiert. Zusätzlich ergaben sich signifikante Assoziationen zur Anzahl an GR (p 0,001), zu GS, die gefährdete körperliche Selbstständigkeit anzeigen, wie Instabilität (p 0,001) und chronische Schmerzen (p = 0,008), sowie GR und GS, die Einfluss auf das Wohlbefinden der Patienten haben, wie Isolation (p 0,001), Depression (p 0,001) und emotionale Ressourcen (p = 0,002).Zum ersten Mal konnte gezeigt werden, dass Lebensqualität, gemessen mittels HRQoL, signifikant mit einem spezifischen Profil von Risiko- und protektiven Faktoren wie GS und GR assoziiert ist. Zur Verbesserung der Lebensqualität sollten eine gezielte und patientenzentrierte Diagnose und Therapie von GS sowie die Stabilisierung von GR auch in nichtgeriatrischen Versorgungsstrukturen angestrebt werden.

Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions. Treatment of non-ciliated cells with tumor necrosis factor (TNF) α and the SMAC mimetic birinapant resulted in Ripk1-dependent cell death, while viability of ciliated cells was almost not affected. Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3. Moreover, combined treatment of ciliated and non-ciliated cells with TNFα and cycloheximide induced a cell death response that could be partially rescued with emricasan in ciliated cells. In contrast, non-ciliated cells responded with pronounced cell death that was blocked by necroptosis inhibitors. Consistently, combined treatment with interferon-γ and emricasan induced cell death only in non-ciliated cells. Mechanistically, enhanced necroptosis induced by loss of cilia could be explained by induction of Ripk3 and increased abundance of autophagy components, including p62 and LC3 associated with the Ripk1/Ripk3 necrosome. Genetic ablation of cilia in renal tubular epithelial cells in mice resulted in TUNEL positivity and increased expression of Ripk3 in kidney tissue. Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.

There is no univocal standardized strategy to predict outcomes and stratify risk of SARS-CoV-2 infected patients, notably in emergency departments. Our aim is to develop an accurate indicator of adverse outcomes based on a retrospective analysis of a COVID-19 database established at the Emergency Department (ED) of a North-Italian hospital during the first wave of SARS-CoV-2 infection. Laboratory, clinical, psychosocial and functional characteristics including those obtained from the Braden Scale—a standardized scale to quantify the risk of pressure sores which takes into account aspects of sensory perception, activity, mobility and nutrition—from the records of 117 consecutive patients with swab-positive COVID-19 disease admitted to the Emergency Medicine ward between March 1, 2020 and April 15, 2020 were included in the analysis. Adverse outcomes included admission to the Intensive Care Unit (ICU) and in-hospital death. Among the parameters collected, the highest cutoff sensitivity and specificity scores to best predict adverse outcomes were displayed by lactate dehydrogenase (LDH) blood value at admission > 439 U/L, Horowitz Index (P/F Ratio)

The management of older and multimorbid patients with complex care requires a personalised and comprehensive approach. The main diagnosis is often registered as the cause of hospitalisation, yet poor health-related quality of life (HRQoL) as well as multimorbidity may represent the underlying cause and markedly influence prognosis. To analyse the association of HRQoL and clinical prognosis over time as assessed by a Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI) in older patients admitted to the emergency department (ED). We used data from the prospective MPI–HOPE (Influence of the MPI on the Hospitalisation of Older Patients admitted to the Emergency department) study. Data from 165 patients (≥ 75 years) admitted to the ED of the University Hospital of Cologne, Germany, between Oct 2017 and Jan 2018 were included. Clinical prognosis was calculated by the MPI and HRQoL by the EQ5D-5L. Follow-up interviews assessed HRQoL up to 6 months after discharge. Most patients were multimorbid and presented with several geriatric syndromes. At admission, HRQoL was highest in patients with the best clinical prognosis. The MPI showed a negative correlation with the EQ-Index at admission (rs(86) = − 0.50, p

Geriatric syndromes (GS) do not fit into discrete disease categories and are often underdiagnosed in hospitalized older adults. Geriatric resources (GR) are also not routinely collected in clinical settings, although this may potentiate the beneficial effects of clinical decisions. The prognostic relevance of GS and GR has never been systematically evaluated through clinical tools developed for clinical decision purposes. To ascertain the impact of common GS and GR on patients’ prognosis as assessed by means of the comprehensive geriatric assessment (CGA)-based Multidimensional Prognostic Index (MPI). One hundred and thirty-five hospitalized patients aged 70 years and older underwent a CGA evaluation with calculation of the MPI on admission and discharge. Accordingly, patients were subdivided in low (MPI-1, score 0–0.33), moderate (MPI-2, score 0.34–0.66), and severe (MPI-3, score 0.67–1)-risk of mortality at 1 month and 1 year. Nine GR and 17 GS were identified and collected accordingly. A lower number of GS and a higher number of GR were shown to be highly significantly correlated with a lower MPI, as well as years of education, grade of care, and number of medications independent of age, sex and number of GS or GR. Underweight and obesity according to the BMI were significantly correlated to higher number of GS. Patients with more GR had a significantly higher chance of being discharged home. The MPI evaluation together with GS and GR in acute care for older patients should be encouraged to improve clinical decision-making.

Epidermal development is a complex process of regulated cellular proliferation, differentiation, and tightly controlled cell death involving multiple cellular signaling networks. Here, we report a first description linking the AAA+ (ATPases associated with various cellular activities) superfamily protein Ruvbl1 to mammalian epidermal development. Keratinocyte-specific Ruvbl1 knockout mice (Ruvbl1fl/flK14:Cretg) show a severe phenotype including dramatic structural epidermal defects resulting in the loss of the functional skin barrier and perinatal death. Thus, Ruvbl1 is a newly identified essential player for the development of differentiated epidermis in mice.

Patients with end-stage renal disease (ESRD) requiring hemodialysis are typically characterized by multimorbidity and increasingly by advanced age; however, there are few data on their geriatric needs. The aim of the study was to evaluate the clinical characteristics of a large cohort of incident patients in ambulatory hemodialysis units with a particular focus on those aged over 80 years in Germany. The electronic patient registry of the Board of Trustees (Kuratorium) for Dialysis and Kidney Transplantation (KfH) was searched for all patients who began hemodialysis in 1 of the 191 units between 2007 and 2013 and were 65 years and older. Patients were analyzed by age (65–79 years and ≥80 years) for clinical and biochemical characteristics, mortality, quality of life and hospitalizations. Of the 21,355 incident patients, a total of 13,872 (65%) were over 65 years old, with 9998 (46.8%) aged between 65 and 79 years and 3874 (18.1%) patients 80 years or older (oldest old). The spectrum of morbidity was comparable between the two age groups but there was a significantly higher prevalence of anemia, hypoalbuminemia and multimorbidity (>four comorbidities) in the older age group. Median survival was 4.5 years (1638 days) in the younger age group and 2.7 years (978 days) in the older group. Almost half of the patients experienced at least one episode of hospitalization during the first year but there were no significant differences between the age groups (45.9% in younger vs. 47% in older patients). In the older age group 463 (12%) patients survived more than 5 years after initiation of hemodialysis despite the presence of multiple risk factors for adverse clinical outcome. More than half of the chronic ambulatory hemodialysis patients were of advanced age and had a very high burden of multimorbidity. Nevertheless, a subgroup of ERSD patients over 80 years old survived at least 5 years on hemodialysis despite the presence of multiple risk factors for adverse clinical outcome. Identification of these patients as well as optimized care for frail hemodialysis patients will require application of geriatric assessment tools in addition to traditional parameters in nephrology. The development and validation of such tools should be the subject of further clinical studies.

Background Transplant failure requires the consideration of numerous potential causes including rejection, acute tubular necrosis, infection, and recurrence of the original kidney disease. Kidney biopsy is generally required to approach these differential diagnoses. However, the histopathological findings on their own do not always lead to a definite diagnosis. Consequently, it is crucial to integrate them with clinical findings and patient history when discussing histopathological patterns of injury. The histopathologic finding of a membranoproliferative glomerulonephritis (MPGN) is one of the most challenging constellations since it does not refer to a specific disease entity but rather reflects a pattern of injury that is the result of many different causes. Whilst MPGN is occasionally classified as immune complex mediated, careful evaluation usually reveals an underlying disorder such as chronic infection, plasma cell dyscrasia, complement disorders, and autoimmune disease. Case presentation We describe the case of a 43-year-old woman who was referred to us because of a slowly rising serum creatinine 4 years after kidney transplantation. As in the native kidney, the biopsy revealed an MPGN pattern of injury. The cause of this finding had not been established prior to transplantation leading to a classification as idiopathic MPGN in the past. Further workup at the time of presentation and allograft failure revealed chronic infection of a ventriculoatrial shunt as the most probable cause. Conclusion This case underlines the fact that MPGN is not a disease but a histopathological description. Consequently, the causative disorder needs to be identified to avoid kidney failure and recurrence after transplantation.

Bei Patienten mit arterieller Hypertonie sind Nierenerkrankungen haufig. Einerseits verursacht die Hypertonie sehr oft Nierenschaden, andererseits konnen aber auch Nierenerkrankungen selbst fur die Entstehung der arteriellen Hypertonie verantwortlich sein. Bei allen Hypertonikern ist daher eine regelmasige Kontrolle der Nierenfunktion unerlasslich. Lesen Sie hier, welche Parameter Sie im Auge behalten sollten!

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extra-renal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.

A new study reports that a single blood test can be used to rule out the development of pre-eclampsia in women in whom the syndrome is suspected. Early interventions for pre-eclampsia are not yet available, but this finding is likely to change the approach to diagnosis of hypertensive disorders in pregnancy.

Advances in molecular genetics have led to the identification of more than 70 different genes involved in the development of cystic kidney diseases. Most of these diseases are rare, and interpreting the resultant plethora of disease-causing mutations requires a methodical and meticulous approach to differential diagnosis. In this Review we discuss a clinical approach to the diagnosis of cystic kidney diseases in adults, for use by nephrologists. This approach is based upon a thorough clinical evaluation, which considers both kidney phenotype and extrarenal manifestations of the underlying disorder, in combination with genetic testing in selected patients. In our view, cystic kidney disease can (in the majority of patients) be reliably classified on the basis of clinical findings. We therefore propose that defining clinical situations to precipitate the initiation of genetic testing is mandatory and cost-effective. New techniques such as next-generation sequencing will facilitate the diagnosis of cystic kidney diseases in the future, increasing diagnostic safety in a subset of patients. In renal tumour syndromes, genetic testing is warranted.

The purpose of this cross-sectional prospective study was to determine the prevalence of anemia among elderly hospitalized patients in Germany and to investigate its association with multidimensional loss of function (MLF). One hundred participants aged 70 years or older from two distinct wards (50 each from an emergency department and a medical ward, respectively) underwent a comprehensive geriatric assessment (CGA) consisting of the following six tools: Barthel Index, mini-mental state examination, clock-drawing test, timed up and go test, Esslinger transfer scale, and Daniels test. MLF as an aggregated outcome was diagnosed when three or more tests of the CGA showed an abnormal result. Anemia was defined according to WHO criteria as a hemoglobin (Hb) concentration of

Chronic alterations in calcium (Ca2+) signalling in podocytes have been shown to cause proteinuria and progressive glomerular diseases. However, it is unclear whether short Ca2+ peaks influence glomerular biology and cause podocyte injury. Here we generated a DREADD (Designer Receptor Exclusively Activated by a Designer Drug) knock-in mouse line to manipulate intracellular Ca2+ levels. By mating to a podocyte-specific Cre driver we are able to investigate the impact of Ca2+ peaks on podocyte biology in living animals. Activation of the engineered G-protein coupled receptor with the synthetic compound clozapine-N-oxide (CNO) evoked a short and transient Ca2+ peak in podocytes immediately after CNO administration in vivo. Interestingly, this Ca2+ peak did neither affect glomerular perfusion nor filtration in the animals. Moreover, no obvious alterations in the glomerular morphology could be observed. Taken together, these in vivo findings suggest that chronic alterations and calcium overload rather than an induction of transient Ca2+ peaks contribute to podocyte disease.

In the version of this article originally published online, the date when Francois Mauriceau published one of the earliest descriptions of pre-eclampsia was incorrectly stated to be 1637, which is actually his year of birth. The work was published in 1668. This error has been corrected in the PDF and HTML versions of the article.

New research suggests that rigorous blood pressure control is beneficial in early autosomal dominant polycystic kidney disease (ADPKD). Although a positive effect on the rate of decline of estimated glomerular filtration rate remains to be demonstrated, this study is likely to change current treatment strategies for young patients with ADPKD.

MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA-processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4-6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA-dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans.

Background Non-coding RNAs have gained increasing attention during the last decade. The first large group of non-coding RNAs to be characterized systematically starting at the beginning of the 21st century were small oligonucleotides—the so-called microRNAs (miRNAs). By now we have learnt that microRNAs are indispensable for most biological processes including organogenesis and maintenance of organ structure and function. The role of microRNAs has been studied extensively in the development of a number of organs, so far most studies focussed on e.g. the heart or the brain whilst the role of microRNAs in the development and maintenance of complex epithelial organs is less well understood. Furthermore most analyses regarding microRNA function in epithelial organs employed conditional knockout mouse models of the RNAse III Dicer to abrogate microRNA biogenesis. However, there is increasing evidence for Dicer to have multiple functions independent from microRNA maturation. Therefore Dicer independent models are needed to gain further insight into the complex biology of miRNA dependent processes. Results Here we analyze the contribution of microRNA-dependent transcriptional control in Pax8-expressing epithelial cells. Pax8 is a transcription factor that is crucial to the development of epithelial organs. The miRNA machinery was disrupted by crossing conditional DiGeorge syndrome critical region 8(Dgcr8) fl/fl mice to Pax8Cre mice. The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm. Dgcr8 fl/fl; Pax8Cre+ knockout mice died prematurely, developed massive hypothyroidism and end stage renal disease due to a loss of miRNAs in Pax8 expressing tissue. Conclusion Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals. These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model. Electronic supplementary material The online version of this article (doi:10.1186/s12867-016-0064-x) contains supplementary material, which is available to authorized users.

The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.

New work has identified networks of protein interactions at the transition zones of cilia. These discoveries provide insights into the molecular pathogenesis of ciliopathies and illustrate the power of linking proteomics technologies with human genetics to uncover critical disease pathways.

Genetic Testing Comes of Age: WT1 Mutations in Steroid-Resistant Nephrotic Syndrome: Commentary on the article by Mucha et al. on page 325

Nature Reviews Molecular Cell Biology 8, 880–893 (2007); doi:10.1038/nrm2278 The authors would like to add the following text (in italics) and references (see references *,‡ and § below) to the article, and include a change to Figure 2a. On page 883 of the article, in the first paragraph following the main heading 'Disorders of development and growth', the text and references should read as follows