Sialoglycan-binding enveloped viruses often possess receptor-destroying activity to avoid being immobilized by non-functional decoy receptors. Sialic acid (Sia)-binding paramyxoviruses contain a ...hemagglutinin-neuraminidase (HN) protein that possesses both Sia-binding and -cleavage activities. The multivalent, dynamic receptor interactions of paramyxovirus particles provide virion motility and are a key determinant of host tropism. However, such multivalent interactions have not been exhaustively analyzed, because such studies are complicated by the low affinity of the individual interactions and the requirement of high titer virus stocks. Moreover, the dynamics of multivalent particle-receptor interactions are difficult to predict from Michalis-Menten enzyme kinetics. Therefore, we here developed Ni-NTA nanoparticles that multivalently display recombinant soluble HN tetramers via their His tags (HN-NPs). Applying this HN-NP platform to Newcastle disease virus (NDV), we investigated using biolayer interferometry (BLI) the role of important HN residues in receptor-interactions and analyzed long-range effects between the catalytic site and the second Sia binding site (2SBS). The HN-NP system was also applicable to other paramyxoviruses. Comparative analysis of HN-NPs revealed and confirmed differences in dynamic receptor-interactions between type 1 human and murine parainfluenza viruses as well as of lab-adapted and clinical isolates of human parainfluenza virus type 3, which are likely to contribute to differences in tropism of these viruses. We propose this novel platform to be applicable to elucidate the dynamics of multivalent-receptor interactions important for host tropism and pathogenesis, particularly for difficult to grow sialoglycan-binding (paramyxo)viruses.
Brain organoids are highly complex multi-cellular tissue proxies, which have recently risen as novel tools to study neurodegenerative diseases such as Parkinson's disease (PD). However, with ...increasing complexity of the system, usage of quantitative tools becomes challenging.
The primary objective of this study was to develop a neurotoxin-induced PD organoid model and to assess the neurotoxic effect on dopaminergic neurons using microscopy-based phenotyping in a high-content fashion.
We describe a pipeline for a machine learning-based analytical method, allowing for detailed image-based cell profiling and toxicity prediction in brain organoids treated with the neurotoxic compound 6-hydroxydopamine (6-OHDA).
We quantified features such as dopaminergic neuron count and neuronal complexity and built a machine learning classifier with the data to optimize data processing strategies and to discriminate between different treatment conditions. We validated the approach with high content imaging data from PD patient derived midbrain organoids.
The here described model is a valuable tool for advanced in vitro PD modeling and to test putative neurotoxic compounds.
•We describe an interdisciplinary approach to assess the effect of 6-OHDA on dopaminergic neurons in midbrain organoids.•3D high-content screening of organoids was used to extract morphometric features of dopaminergic neurons.•Machine learning classifier was applied on the high-content data to predict neurotoxin-induced perturbations.
The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components ...localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo
MCM6
missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo
MCM6
variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo
MCM6
variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of
MCM6
variants in the diagnostic arsenal of NDD.
Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as ...first-line treatment for gl-ILD, but evidence for their efficacy is lacking.
This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results.
Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed.
Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts.
Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.
Avian species, through their trophic relationships, may represent ideal indicators for assessing environmental health. In this study several assays of immune function in young passerines are ...validated and compared. From 6 to 10 days of age, zebra finch nestlings (Taeniopygia guttata) were given daily oral doses of Oil Sands tailings water (CT), an immunosuppressant dexamethasone, or phosphate-buffered saline. At 9–10 days of age, a phytohemagglutinin (PHA) skin test of immune function was conducted; at 11 days of age, five chicks from each group were euthanized for gross and histopathologic examination of immune system organs. The remaining birds were vaccinated with sheep red blood cells (srbc) to evaluate antibody-mediated immunity. The main findings were that in 10-day-old nestlings, T lymphocytes were sensitive to PHA stimulation, while B lymphocytes were unable to respond to srbc; that hematocrit was approximately 30% lower than in mature birds; that precision of leucocrit determination was heavily technique-dependent; that endogenous steroids increased the total leucocrit, while exogenous steroids increased heterophil and decreased lymphocyte counts, thus increasing H:L; that dexamethasone exposure temporarily reduced growth rate; that CT exposure stimulated germinal cell development in the bursa of Fabricius; and that dexamethazone and CT exposure were associated with decreased splenic white pulp formation.
Identifying the potential effects of industrially formed wetlands on waterfowl populations is important for assessing the suitability of such wetlands in industrial reclamation strategies. Mallard ...ducklings were held in situ on two industrially formed wetlands and one reference wetland in northern Alberta, Canada. Duckling mass and skeletal size were measured at regular intervals over 33 d, and blood was collected to investigate the analysis of plasma metabolites (triglyceride and glycerol) as an indicator of physiological condition. In repeated‐measures analysis of variance (ANOVA), multivariate ANOVA, and subsequent multiple‐comparisons tests, body mass and skeletal size were significantly lower in ducklings maintained on the industrial wetland after 2, 5, 9, and 13 d of exposure. In this situation, plasma metabolite analysis did not provide additional information on mass‐independent condition. We conclude that if the observed differences in growth and size translate into a decreased survival of juvenile waterfowl inhabiting these wetlands, then populations of these birds in the area could be negatively affected. We emphasize the importance of field‐based ecological research in toxicological studies of wildlife.
Chinas economic growth is gradually slowing as the structural transformation of the economy continues. Output grew by 7.7 percent in 2013, matching its 2012 growth rate and exceeding the governments ...7.5 percent indicative target. In recent months economic activity, including industrial production, started to show signs of acceleration. The recent acceleration, expected to continue into the next two quarters, is partly reflecting the effect of new growth-supporting measures, robust consumption, and a recovery of external demand. Chinas growth will continue to moderate over the medium term, and the structural shifts will become more evident. Growth in China is expected to decrease marginally to 7.6 percent in 2014 and 7.5 percent in 2015, from 7.7 percent in 2013. Fiscal and financial sector reforms are needed to address financial stability risks in the medium run. The first task involves effectively managing the process of rapid credit growth, including less well-regulated shadow banking system. The second involves gradual and orderly deleveraging of large stock of local government debt accumulated through off-budget and quasi-fiscal platforms.
Book Reviews Adelaar, K. Alexander; Collins, James T.; Adelaar, K. Alexander ...
Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia,
1998, Volume:
154, Issue:
4
Book Review
Peer reviewed
- K. Alexander Adelaar, James T. Collins, Bibliografi dialek Melayu di pulau Sumatera. Kuala Lumpur: Dewan Bahasa dan Pustaka (Kementerian Pendidikan Malaysia), 1995, xliii + 201 pp. Siri Monograf ...Bibliografi Sejarah Bahasa Melayu. - K. Alexander Adelaar, James T. Collins, Bibliografi dialek Melayu di pulau Jawa, Bali dan Sri Lanka. Kuala Lumpur: Dewan Bahasa dan Pustaka (Kementerian Pendidikan Malaysia), 1995, xxxvii + 213 pp. Siri Monograf Bibliografi Sejarah Bahasa Melayu. - K. Alexander Adelaar, James T. Collins, Bibliografi dialek Melayu di Indonesia Timur. Kuala Lumpur: Dewan Bahasa dan Pustaka (Kementerian Pendidikan Malaysia), 1996, xxx + 103 pp. Siri Monograf Bibliografi Sejarah Bahasa Melayu. - K. Alexander Adelaar, James T. Collins, Bibliografi dialek Melayu di pulau Borneo. Kuala Lumpur: Dewan Bahasa dan Pustaka (Kementerian Pendidikan Malaysia), 1990, xxviii + 100 pp. Siri Monograf Bibliografi Sejarah Bahasa Melayu. - Freek L. Bakker, Samuel Wälty, Kintamani; Dorf, Land und Rituale; Entwicklung und institutioneller Wandel in einer Bergregion auf Bali. Münster: Lit Verlag, 1997, xii + 352 pp. - René van den Berg, Linda Barsel, The verb morphology of Mori, Sulawesi. Canberra: Department of Linguistics, Research School of Pacific and Asian Studies, Australian National University, 1994, x + 139 pp. Pacific Linguistics Series B-111. - Martin van Bruinessen, Darul Aqsha, Islam in Indonesia; A survey of events and developments from 1988 to March 1993. Jakarta: INIS, 1995, 535 pp., Dick van der Meij, Johan Hendrik Meuleman (eds.) - Martin van Bruinessen, Niels Mulder, Inside Indonesian society; Cultural change in Java. Amsterdam: Pepin Press, 1996, 240 pp. Previously published Bangkok, Duang Kamol, 1994. - Matthew Isaac Cohen, Craig A, Lockard, Dance of life; Popular music and politics in Southeast Asia. Honolulu: University of Hawai’i Press, 1998, xix + 390 pp. - Will Derks, Tenas Effendy, Bujang Tan Domang; Sastra lisan orang Petalangan. Yogyakarta: Yayasan Benteng Budaya/Ecole Francaise d’Extrême Orient/The Toyota Foundation, 1997, 818 pp. Al Azhar and Henri Chambert-Loir (eds). - Will Derks, Philip Yampolsky, Music from the forests of Riau and Mentawai. Recorded and compiled by Philip Yampolsky; annotated by Hanefi, Ashley Turner, and Philip Yampolsky. Washington, D.C.: Smithsonian Folkways, 1995. Music of Indonesia 7SF; CD 40423. - Will Derks, Philip Yampolsky, Melayu music of Sumatra and the Riau Islands: Zapin, Mak Yong, Mendu, Ronggeng. Recorded, compiled , and annotated by Philip Yampolsky. Washington D.C.: Smithsonian Folkways, 1996. Music of Indonesia 11 SF; CD 40427. - Rens Heringa, Roy W. Hamilton, Gift of the cotton maiden; Textiles of Flores and the Solor Islands. Los Angeles: Fowler Museum of Cultural History, University of California, 1994, 287 pp. - Bernice de Jong Boers, Willemijn de Jong, Geschlechtersymmetrie in einer Brautpreisgesellschaft; Die Stoffproduzentinnen der Lio in Indonesien. Berlin: Reimer, 1998, 341 pp. - C. de Jonge, A.Th. Boone, Bekering en beschaving; De agogische activititeiten van het Nederlandsch Zendelinggenootschap in Oost-Java (1840-1865). Zoetermeer: Boekencenturm, 1997, xiv + 222 pp. - Nico Kaptein, Peter G. Riddell, Islam; Essays on scripture, thought and society; A Festschrift in honour of Anthony H. Johns. Leiden: Brill, 1997, xliii + 361 pp., Tony Street (eds.) - Hugo Klooster, Janny de Jong, Niet-westerse geschiedenis; Benaderingen en thema’s. Assen: Van Gorcum, 1998, 185 pp., Gé Prince, Hugo s’Jacob (eds.) - Jean Robert Opgenort, L. Smits, The J.C. Anceaux collection of wordlists of Irian Jaya languages, B: Non-Austronesian (Papuan) languages (Part I). Leiden/Jakarta: Department of Languages and Cultures of Southeast Asia and Oceania, Rijksuniversiteit Leiden/Irian Jaya Studies Interdisciplinary Research Programme (IRIS), 1994, vi + 281 pp. Irian Jaya Source Materials 9 (Series B No. 3)., C.L. Voorhoeve (eds) (eds.) - Pim Schoorl, Albert Hahl, Gouverneursjahre in Neuguinea. Edited by Wilfried Wagner. Hamburg: Abera Verlag Meyer, 1997, xxxi + 230 pp. - Elly Touwen-Bouwsma, Dieuwke Wendelaar Bonga, Eight prison camps; A Dutch family in Japanese Java. Athens, Ohio: University Center for International Studies, 1996, xii + 219 pp. - Freek Colombijn, Anthony J. Whitten, The ecology of Sumatra. Yogyakarta: Gadjah Mada University Press, 1987 First edition 1984, xxiii + 583 pp., photographs, figures, tables, index., Sengli J. Damanik, Jazanul Anwar (eds.) - David Henley, Anthony J. Whitten, The ecology of Sulawesi. Yogyakarta: Gadjah Mada University Press, 1987, xxi + 777 pp., Muslimin Mustafa, Gregory S. Henderson (eds.) - Peter Boomgaard, Tony Whitten, The ecology of Java and Bali. Singapore: Periplus Editions, 1996, xxiii + 969 pp. The Ecology of Indonesia Series 2., Roehayat Emon Soeriaatmadja, Surya A. Afiff (eds.) - Han Knapen, Kathy MacKinnon, The ecology of Kalimantan. Singapore: Periplus Editions, 1996, xxiv + 802 pp., tables, figures, boxes, index. The Ecology of Indonesia Series 3., Gusti Hatta, Hakimah Halim (eds.) - Bernice de Jong Boers, Manon Ossewiejer, Kathryn A. Monk, The ecology of Nusa Tenggara and Maluku. Singapore: Periplus Editions, Oxford: Oxford University Press, 1997, xvii + 966 pages, tables, figures, boxes, annexes, appendixes, index. The Ecology of Indonesia Series 5., Yance de Fretes, Gayatri Reksodiharjo-Lilley (eds.) - Freek Colombijn, Tomas Tomascik, The ecology of the Indonesian seas 2 volumes. Hong Kong: Periplus, 1997, xiv + vi + 1388 pp., photographs, figures, tables, indexes. The Ecology of Indonesia Series 7-8., Anmarie Janice Mah, Anugerah Nontji (eds.)
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