Genetics in Medicine

Prenatal protein deficiency causes behavioral and cognitive dysfunctions in children. The deficits could be caused by altered acquisition and processing of sensory information in the brain. Although GABAergic neurons are the key regulators of neuronal activity, the effect of prenatal protein deficiency on GABA neurons in the brain is largely unknown. We fed pregnant mice diets with one-third (7%) or half (10%) the normal protein requirement (20% protein). After birth, the pups were fostered with normally fed lactating females. We used transgenic mice to show that protein deficiency in pregnant dams fed a 7% protein diet affected the number and distribution of GABA neurons in the somatosensory barrel cortex and individual cortical layers during early postnatal development of pups. If the mothers were fed a 10% protein diet, the effects on GABA neurons were much less. Development of barrels was also affected in pups born to mothers fed the 7% protein diet, but not the 10% group. In addition, high protein deficiency, i.e., the 7% protein diet, affected conception, hampered gestational weight gain, induced resorption of embryos, reduced litter sizes, and increased cannibalism, which was not observed in females on 10% protein diet.

The bulk of malaria rapid diagnostic tests (RDTs) target Plasmodium falciparum histidine-rich protein 2 (PfHRP2), but several reports have shown that sequence variations in this protein are associated with false-negative RDT results. The polymorphism of PfHRP2/3 was analyzed from Cameroonian and Indian P. falciparum isolates. Cameroon and India are two of eleven countries with the highest malaria burden. Exon 2 of  pfhrp 2/3 genes were PCR-amplified, and the amplicons were purified and sequenced. A total of 25 PfHRP2 and 12 PfHRP3 novel repeat type variants were found. The nature and organization of PfHRP3 sequences were quite similar between Cameroon and India. Some structurally unique PfHRP2/3 sequences, characterized by a high proportion of proline (5.8–10.3%) for PfHRP2, and two non-repeat regions for PfHRP3, were found in both countries. Most of the Cameroonian isolates belonged to group B (66.7%), while the Indian isolates belonged to group C (69.2%) (p=0.03). Three epitope motifs (AHHAHHA, HATDAHH, and YAHHAHHA) were found in all Cameroonian and Indian PfHRP2 sequences. Mutations observed in unique sequences were mainly associated with alterations of helical structures in the PfHRP2 C-terminal region. The high genetic diversity, epitope availability, and structural basis patterns found here could help develop the next generation of RDTs with improved quality.

The transcription factors PAX6 and LHX2 play fundamental roles in mammalian cerebral cortical development. Loss of either factor causes depletion of the cortical progenitor pool and reduction of neurogenesis of later-born cortical neurons. We compared the chromatin occupancy of PAX6 and LHX2 and transcriptional dysregulation upon loss of each factor to analyze whether they function via common gene regulatory networks. We identified common direct and indirect targets that were dysregulated either concordantly or discordantly, based on whether their expression showed similar up- or downregulation upon loss of either factor. Finally, we examined single-cell RNA-seq datasets from neocortical progenitors to identify the cell types within which each common direct/indirect and concordantly/discordantly regulated target gene is expressed as cortical progenitors undergo neurogenesis. Our analysis shows that PAX6 and LHX2 have several common targets that suggest similar pathways for progenitor maintenance, but the regulation of neurogenesis may occur via at least partially non-overlapping pathways. Furthermore, each factor functions to suppress the expression of a set of common Cajal-Retzius cell-specific and interneuron-specific genes which are not normally expressed by cortical progenitors. Together, our analysis offers experimentally testable hypotheses for how PAX6 and LHX2 may execute their critical roles.

The neuromuscular junction (NMJ) is crucial for understanding the fundamentals of synaptic transmission and activity. Various modulators operate within neuronal circuits, from sensory to motor neurons, to influence synaptic transmission at the NMJ. This study sheds light on the regulation of sensory-evoked cholinergic neurotransmission at motor neurons orchestrated by CASY-1, the mammalian calsyntenin orthologue. We report that the increased excitation–inhibition (E-I) ratio at the NMJ in casy-1 mutants is likely due to its interactions with neuromodulators in sensory neurons. We explored the intricate genetic interactions of CASY-1 with the neuropeptide FLP-21 and its receptor, NPR-1, both of which display simultaneous alterations in cholinergic signaling at the NMJ. Through genetic, pharmacological, and bioimaging-based experiments, we proposed a mechanism by which CASY-1 potentially interacts with the neuropeptide-carrying vesicles to regulate synaptic transmission. The nematode Caenorhabditis elegans serves as an ideal model system for this study, enabling detailed insights into neuromodulatory mechanisms in the neuronal circuit.

The Johanson–Blizzard syndrome (JBS) is a complex autosomal recessive disorder that manifests through a spectrum of symptoms, with deficiencies in the ubiquitin–protein ligase E3 component N-recognin 1 (UBR-1) at its genetic core. Despite its clinical significance, the molecular intricacies of UBR-1’s role in JBS remain largely elusive, presenting a formidable challenge in devising targeted treatments. The nematode Caenorhabditis elegans, with its genetic tractability and conservation of fundamental biological mechanisms, emerges as an invaluable model for unravelling the molecular underpinnings of JBS. This review integrates the latest discoveries from C. elegans studies, shedding light on UBR-1’s multiple functions: its regulatory impact on cellular pathways and, particularly, its crucial involvement in glutamate metabolism. By assessing the contributions of these studies to our understanding of JBS, this review highlights the potential significance of glutamate metabolic dysfunction in JBS pathogenesis.

In response to unfavourable conditions and environmental duress, Caenorhabditis elegans follows an alternative developmental stage called the dauer larva, which is associated with various metabolic changes. Dauers can survive in harsh conditions for several months. They resume their development on returning to favourable conditions. This study investigates the impact of altered insulin signalling on memory in post-dauer C. elegans. Our major findings reveal significant deficits in both short- and long-term associative memory in post-dauer nematodes. Through behavioural assays, we demonstrate a robust impairment in memory retrieval, indicating a potential link between the post-dauer state and cognitive dysfunction. Strikingly, we identify that the short-term memory deficit observed in post-dauer worms can be ameliorated by the administration of exogenous insulin. The findings underscore the critical role of insulin signalling in modulating memory processes in post-dauer C. elegans, shedding light on the molecular mechanisms governing memory defects in this developmental stage.

Initiation of protein translation is one of the key steps in protein synthesis carried out by translation initiation factors in conjunction with ribosomes. The roles and mechanisms of these initiation factors in prokaryotic and eukaryotic protein synthesis are well understood. However, they are only beginning to be understood in trypanosomatids. Trypanosomatid translation initiation factors have differences with eukaryotic translation initiation factors, e.g., they have six keIF4Es and five keIF4Gs with significant novelty in their structure–function relationships. The trypanosomatid keIF4Es and keIF4Gs are the most well studied initiation factors. However, a trypanosomatid orthologue of the eukaryotic initiation factor 4B (eIF4B) has not been previously reported. In this report, using bioinformatics tools and homology modelling/structure prediction studies, we identified trypanosomatid double RNA binding domain protein 9s (DRBD9s) as likely orthologues of eIF4Bs.

Neuroinformatics, an interdisciplinary field integrating neuroscience and informatics, plays a crucial role in understanding the complexities of the brain and neurological diseases such as Alzheimer’s disease (AD). This review explores the applications, databases, and tools used in neuroinformatics, focusing on their role in AD research. Neuroinformatics facilitates data integration, analysis, and modeling, enabling researchers to unravel the underlying mechanisms of AD pathology. Various databases and tools provide access to neuroimaging, and genetic and clinical data, facilitating collaborative research and the development of diagnostic and therapeutic strategies. Neuroinformatics holds promise in advancing our understanding and treatment of AD, offering insights into disease progression, biomarker identification, and personalized medicine approaches.