and mutations in a patient with a neurodevelopmental disorder and immunodeficiency.

The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) 'Intellectual Disability, Autosomal Dominant 57' (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown.

Rational optimization of a transcription factor activation domain inhibitor.

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening.

Identification of a mutation in associated with a neurodevelopmental disorder and immunodeficiency.

Background: The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with 'Intellectual Disability, Autosomal Dominant 57' (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown.

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood.

Pathway-specific effects of ADSL deficiency on neurodevelopment.

Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms.

Hereditary Multiple Exostoses-A Comprehensive Examination of a 4-Year-Old Dutch Warmblood Male With Maternal Links to HME in First and Second Generations.

Hereditary multiple exostoses (HME) is a condition rarely diagnosed in horses, which has not been previously reported in Dutch Warmblood horses. Its presentation resembles that diagnosed in humans, and it is predominantly active during periods of skeletal maturation. This case study reports a link between a granddam with no obvious HME lesions and its first and second generations presenting with HME, albeit with different sires.

Seasonal differences in cytokine expression in the skin of Shetland ponies suffering from insect bite hypersensitivity.

Insect bite hypersensitivity (IBH) in horses is a seasonal, IgE-mediated, pruritic skin disorder primarily caused by Culicoides spp. We hypothesize that a mixed Th2/Th1-type immune status, off season, alters into Th2-dominated immune reactivity in the skin of IBH-affected ponies in the IBH season. To study these immune response patterns Culicoides-specific IgE levels, skin histopathology and cytokine and transcription factor mRNA expression (IL4, IL10, IL13, IFNγ, FoxP3 and CD3(ζ)) in lesional and non-lesional skin of ponies affected by IBH in the IBH season were compared with those of the same animals off season and those in skin of healthy ponies in both seasons.

Tracing systems used during the epidemic of classical swine fever in the Netherlands, 1997-1998.

Any outbreak of an animal disease classified as a List A disease by the Office International des Epizooties, such as classical swine fever (CSF), has severe consequences for animal welfare, livestock production, exports of animals and animal products and the environment. Experience shows that early detection and response to a suspected disease outbreak will maximise the effectiveness of the emergency response actions and minimise the social, economic and environmental costs associated with the outbreak. The development and implementation of measures designed to minimise the risk of diseases entering a country or region has been the predominant animal health management strategy in most countries.

Transmission of classical swine fever virus by artificial insemination during the 1997-1998 epidemic in The Netherlands: a descriptive epidemiological study.

In the course of the 1997-1998 CSF epidemic in the Netherlands, two semen collection centres (SCC) became infected. As an eradication strategy for an acute crisis situation, it was concluded that all semen of the boars at the SCCs collected and distributed in the risk period of 28 January to 7 March 1997 was potentially contaminated (suspect semen). As a consequence, a total of 1,680 pig herds, mainly located in the southern part of the Netherlands, were officially declared CSF suspect.

The 1997-1998 epidemic of classical swine fever in the Netherlands.

In 1997, the pig husbandry in the Netherlands was struck by a severe epidemic of classical swine fever (CSF). During this epidemic 429 CSF-infected herds were depopulated and approximately 1300 herds were slaughtered pre-emptively. In addition millions of pigs of herds not CSF-infected were killed for welfare reasons (over crowding or overweight).

Quantification of the transmission of classical swine fever virus between herds during the 1997-1998 epidemic in The Netherlands.

In this study, we describe a method to quantify the transmission of Classical Swine Fever Virus (CSFV) between herds from data collected during the 1997-1998 epidemic in The Netherlands. From the contacts between infected herds and the serological findings shortly before depopulation, we estimated the week of virus introduction and the length of the period over which the herd emitted virus for each CSFV-infected herd. From these data, we estimated the infection-rate parameter beta (the average number of herds infected by one infectious herd during one week) and the herd reproduction ratio, Rh (the average total number of secondary outbreaks caused by one infectious herd, i.

The classical swine fever epidemic 1997-1998 in The Netherlands: descriptive epidemiology.

The objective of this paper is to describe the severe epidemic of classical swine fever (CSF) in The Netherlands in 1997-1998 under a policy of non-vaccination, intensive surveillance, pre-emptive slaughter and stamping out in an area which has one of the highest pig and herd densities in Europe. The primary outbreak was detected on 4 February 1997 on a mixed sow and finishing pig herd. A total of 429 outbreaks was observed during the epidemic, and approximately 700,000 pigs from these herds were slaughtered.

Classical swine fever in The Netherlands 1997-1998: a description of organisation and measures to eradicate the disease.

The central and regional organisation of the campaign to eradicate the CSF epidemic in The Netherlands in 1997/1998 is described. The main instruments used in the campaign were based on stamping-out and movement restrictions specified by the European Union. Additional instruments were used for the first time, namely, pre-emptive culling of contact and neighbouring farms, compartmentalisation of transport, monthly serological screening in established surveillance areas and supervised repopulation of all farms in the former surveillance zone.

The involvement of the agriculture industry and government in animal disease emergencies and the funding of compensation in western Europe.

In Western Europe, the control and eradication of contagious animal diseases have always been subject to government legislation. In the event of an outbreak, the principal policy is 'stamping-out' (depopulation) of the infected herd. The owner of the herd is usually awarded financial compensation.