The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Economists tackle the challenges of a pandemic.

The COVID-19 pandemic radically and rapidly changed the world, including the world of business economists. Eight NABE members employed in a wide variety of fields discuss how their lives and work were transformed.

Sequential functionalization of pyrazole 1-oxides via regioselective metalation: synthesis of 3,4,5-trisubstituted 1-hydroxypyrazoles.

A range of 3,5-diarylated and 3,4,5-triarylated 2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared by regioselective deprotonation at C-5 or bromine-magnesium exchange at C-3 or C-4 followed by transmetalation with ZnCl(2) and palladium(0)-catalyzed cross-coupling. Furthermore, the metalated pyrazole 1-oxides could be trapped with electrophiles. The sequential metalation/functionalization of the pyrazole 1-oxides may follow the order C-5, C-3, C-4, or alternatively the order C-3, C-5, C-4. The 4-methoxybenzyl group of the functionalized 2-(4-methoxybenzyl)pyrazole 1-oxides could be removed by treatment with TFA and i-Pr(3)SiH in CH(2)Cl(2), providing the corresponding functionalized 1-hydroxypyrazoles.

Unchanged cerebral blood flow and oxidative metabolism after acclimatization to high altitude.

The authors investigated the effect of acclimatization to high altitude on cerebral blood flow and oxidative metabolism at rest and during exercise. Nine healthy, native sea-level residents were studied 3 weeks after arrival at Chacaltaya, Bolivia (5,260 m) and after reacclimatization to sea level. Global cerebral blood flow at rest and during exercise on a bicycle ergometer was measured by the Kety-Schmidt technique. Cerebral metabolic rates of oxygen, glucose, and lactate were calculated by the Fick principle. Cerebral function was assessed by a computer-based measurement of reaction time. At high altitude at rest, arterial carbon dioxide tension, oxygen saturation, and oxygen tension were significantly reduced, and arterial oxygen content was increased because of an increase in hemoglobin concentration. Global cerebral blood flow was similar in the four conditions. Cerebral oxygen delivery and cerebral metabolic rates of oxygen and glucose also remained unchanged, whereas cerebral metabolic rates of lactate increased slightly but nonsignificantly at high altitude during exercise compared with high altitude at rest. Reaction time was unchanged. The data indicate that cerebral blood flow and oxidative metabolism are unaltered after high-altitude acclimatization from sea level, despite marked changes in breathing and other organ functions.