Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Biochemical characterization of chamomile essential oil: Antioxidant, antibacterial, anticancer and neuroprotective activity and potential treatment for Alzheimer's disease.

Alzheimer's disease (AD) causes dementia among older adults, increasing the global burden of dementia. Therefore, this study investigates the potential neuroprotective, antioxidant, and anticancer effects of chamomile essential oil (CCO) in Alzheimer's disease. CCO's main volatile compounds (VOCs) were α-bisabolol, camazulene, and bisabolol oxide A, representing 81 % of all VOCs. CCO scavenged 93 % of DPPH free radicals and inhibited the pathogenic bacteria, i.e., Staphylococcus aureus and Salmonella typhi, besides reducing 89 % of brain cancer cell lines (U87). Eighty albino rats were randomized into four groups: standard control, Alzheimer's disease group caused by AlCl3, and treated groups. The results indicated that the mean value of tumor necrosis factor α (TNF-α), amyloid precursor protein (APP), amyloid beta (Aß), caspase-3, & B-cell lymphoma 2 (Bcl-2) was significantly elevated due to the harmful effect of AlCl3; however, CCO downregulated these values, and this effect was attributed to the considerable volatile compounds and phenolic compounds content. Additionally, CCO rats showed a significant increment in noradrenergic (NE), dopaminergic (DO), and serotoninergic systems with relative increases of 50, 50, and 14 % compared to diseased rats. The brain histology of CCO-treated rats showed a significant reduction in neuronal degeneration and improved brain changes, and its histology was close to that of the control brain. The results indicated that CCO offers a new strategy that could be used as an antioxidant and neuroprotective agent for AD due to its considerable contents of antioxidants and anti-inflammatory compounds.

Anticandidal Activity of a Siderophore from Marine Endophyte Pseudomonas aeruginosa Mgrv7.

An endophytic symbiont P. aeruginosa-producing anticandidal siderophore was recovered from mangrove leaves for the first time. Production was optimal in a succinate medium supplemented with 0.4% citric acid and 15 µM iron at pH 7 and 35 °C after 60 h of fermentation. UV spectra of the acidic preparation after purification with Amberlite XAD-4 resin gave a peak at 400 nm, while the neutralized form gave a peak at 360 nm. A prominent peak with RP-HPLC was obtained at RT 18.95 min, confirming its homogeneity. It was pH stable at 5.0-9.5 and thermally stable at elevated temperatures, which encourages the possibility of its application in extreme environments. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) against Candida spp. Were in the range of 128 µg/mL and lower. It enhanced the intracellular iron accumulation with 3.2-4.2-fold (as judged by atomic absorption spectrometry) with a subsequent increase in the intracellular antioxidative enzymes SOD and CAT. Furthermore, the malondialdehyde (MDA) concentration due to cellular lipid peroxidation increased to 3.8-fold and 7.3-fold in C. albicans and C. tropicalis, respectively. The scanning electron microscope (SEM) confirmed cellular damage in the form of roughness, malformation, and production of defensive exopolysaccharides and/or proteins after exposure to siderophore. In conclusion, this anticandidal siderophore may be a promising biocontrol, nonpolluting agent against waterborne pathogens and pathogens of the skin. It indirectly kills Candida spp. by ferroptosis and mediation of hyperaccumulation of iron rather than directly attacking the cell targets, which triggers the activation of antioxidative enzymes.