Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities. Graphic Abstract: [Figure not available: see fulltext.

Conserved Expression of the Glutamate NMDA Receptor 1 Subunit Splice Variants during the Development of the Siberian Hamster Suprachiasmatic Nucleus

Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to environmental changes in quality/quantity of light over the circadian day and annual cycle

Mutual Solubilities of Ammonium-Based Ionic Liquids with Water and with Water/Methanol Mixture

AbstractOver the last two decades, ionic liquids have gained importance as alternative solvents to conventional VOCs in the field of homogeneous catalysis. This success is not only due to their ability to dissolve a large amount of metal catalysts, but it is also due to their potential to enhance yields of enantiopure products. The art of preparation of a specific enantiomer is a highly desired one and searched for in pharmaceutical industry. This work presents a study on solubility in water and in water/methanol mixture of a set of ILs composed of the bis (trifluoromethylsulfonyl) imide anion and of the N-alkyl-triethyl-ammonium cation (abbrev. [NR,222][NTf2]) with the alkyl chain R ranging from 6 to 12 carbons. Mutual solubilities between ILs and water, as well as between ILs and methanol/water mixture were investigated in detail. These solubilities were measured using two well-known and accurate experimental techniques based on a volumetric and a cloud-point methods. Both methods enabled us to measure the Tx diagrams reflecting the mutual solubilities between water (or water/methanol) and selected ILs in the temperature range from 293.15 to 338.15K. The data were fitted by using the modified Flory-Huggins equation proposed by de Sousa and Rebelo and compared also with the prediction carried out by the Cosmo-RS methodolog

Antisperm Antibodies in Blood Sera of Bulls and Correlations with Age, Breed and Ejaculate Quality

Malaya - Jungle forts (4) Feb. 1956 [Photographer's Note incorrect: 1950]Semang people 'live mostly in peninsular Malaysia and speak an Austro-Asiatic language. In the early 21st century their population was estimated to be approximately 2,000. They are traditional nomadic hunters.'GrayscaleForman Safety Negatives, Box 1

Nowe nieinwazyjne metody alternatywnego określania wydajności komórek termoelektrycznych

Celem pracy jest badanie współczesnych alternatywnych źródeł energii, tj. komórek termoelektrycznych. Sprawność ogniw termoelektrycznych podczas bezpośredniej zamiany ciepła odpadowego na energię elektryczną jest zazwyczaj oceniana za pomocą komórek termoelektrycznych uwzględniając temperaturę ściany, różnicę temperatur pomiędzy ścianami termoelektrycznych komórkowych i parametru materiałowego Z. W artykule przedstawiono alternatywną nieinwazyjną metodę określania efektywności ogniwa termoelektrycznego za pomocą oceny wyników porównawczych pomiarów elektrycznych

A proposal for simplifying the method of evaluation of uncertainties in measurement results

The paper deals with the innovative ways of nonstandard, simplifying applications of the valid method for evaluating uncertainties in measurement results and with the definition of conditions of their usability. The evaluation of a substitute criterion for measurement accuracy by means of a relative difference between the measurand and its reference value is proposed. This nonstandard relative uncertainty is comparable with the overall relative standard uncertainty in the measurement result, and thus the evaluation of it enables other simplifications in the calculations of measurement result uncertainties. The use of the simplified evaluation of measurement results is illustrated in two experiments in measurement of the coefficient of thermal conductivity of an insulating material newly developed for the needs of building practice, namely measurement using commercial instruments, and measurement using a newly developed original measuring instrument