Biology subjects

Brar, G.

Publications and source records attributed to Brar, G..

6 recordsLinked to original sources

bioRxiv2026

Prefoldin function links meiotic chromosome segregation with cellular remodeling and reveals tubulin sensitivity of the meiotic spindle

Faithful chromosome segregation is essential for producing viable gametes during meiosis, a specialized type of cell division compared to mitosis. Unlike mitosis, meiosis involves two consecutive chromosome segregation events without an intervening round of DNA replication. Here we identify Gim3, a subunit of the ubiquitously expressed and conserved prefoldin complex, as a critical regulator of meiotic but not mitotic chromosome segregation in budding yeast. Loss of Gim3 causes profound defects in chromosome segregation and gamete viability through reduced tubulin protein levels, which are also associated with reduced spindle length. In mitosis, however, GIM3 deletion minimally affects spindle length and chromosome segregation, despite similarly reduced tubulin levels in both contexts, highlighting a previously unrecognized difference between the sensitivity of meiotic and mitotic spindles to tubulin abundance. In addition to chromosome segregation defects, gim3{Delta} cells exhibit aberrant meiotic cellular remodeling, including defects in exclusion of age-associated protein aggregates from newly forming gametes. Importantly, experimentally induced meiotic chromosome mis-segregation similarly disturbs cellular remodeling. Together, our findings identify Gim3 as a key factor required for maintaining chromosome segregation integrity during meiosis and reveal a previously unrecognized link between chromosome segregation and meiotic cellular remodeling.

cell biology↗

bioRxiv2024

UPR deficiency in budding yeast reveals a trade-off between ER folding capacity and maintenance of euploidy

The Unfolded Protein Response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to ER stress. While the Ire1 branch of this pathway is highly conserved, it is not thought to be important for cellular homeostasis in the absence of stress. Surprisingly, we found that removal of UPR activity led to pervasive aneuploidy in budding yeast cells, suggesting selective pressure resulting from UPR-deficiency. Aneuploid UPR-deficient cells grew better than euploid cells, but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes, could phenocopy the effects of aneuploidy, indicating that the reason cells require UPR activity to maintain euploidy is to counteract protein folding stress in the ER. In support of this model, aneuploidy in UPR-deficient cells can be prevented by expression of a UPR-independent general ER chaperone. Overall, our results indicate an unexpected role for the UPR in basal cell growth that is sufficiently important for cells to accept the costly trade-off of aneuploidy in the absence of UPR activity.

molecular biology↗

bioRxiv2024

Adaptive diversification through structural variation in barley

Pangenomes are collections of annotated genome sequences of multiple individuals of a species. The structural variants uncovered by these datasets are a major asset to genetic analysis in crop plants. Here, we report a pangenome of barley comprising long-read sequence assemblies of 76 wild and domesticated genomes and short-read sequence data of 1,315 genotypes. An expanded catalogue of sequence variation in the crop includes structurally complex loci that have become hot spots of gene copy number variation in evolutionarily recent times. To demonstrate the utility of the pangenome, we focus on four loci involved in disease resistance, plant architecture, nutrient release, and trichome development. Novel allelic variation at a powdery mildew resistance locus and population-specific copy number gains in a regulator of vegetative branching were found. Expansion of a family of starch-cleaving enzymes in elite malting barleys was linked to shifts in enzymatic activity in micro-malting trials. Deletion of an enhancer motif is likely to change the developmental trajectory of the hairy appendages on barley grains. Our findings indicate that rapid evolution at structurally complex loci may have helped crop plants adapt to new selective regimes in agricultural ecosystems.

plant biology↗

bioRxiv2022

The Free Association Sessions: Perspectives on a Novel Teaching Platform by Final Year Medical Students and Basic Specialist Trainees in Psychiatry.

IntroductionNotwithstanding the many advantages of outcomes-based education within Psychiatry placements in Medical School and Basic Specialist Training within the College of Psychiatry of Ireland, there is limited protected time for broad Reflective Practice that appreciates the complexity of working in the Mental Health setting. Furthermore, there are limitations to the current model of restricting Reflective Practice sessions to the Balint Group Format. MethodsA novel programme of structured Reflective Practice was offered to students in the School of Medicine in The University of Limerick and trainees in the Mid-West Deanery. Six student and fourteen trainee participants were subsequently invited to provide perspectives on the programme via Focus Groups. The study employed an inductive latent phenomenological approach for analysis of qualitative data. ResultsFive major themes emerged: These related to the teaching environment, personal identity, complexity, awareness of cognitive dissonance and the structure of the sessions. There were a number of different perceptions, relating to the participants stage of training. ConclusionsThere was evidence that the structured reflective sessions created a comfortable environment, addressed hierarchy issues and facilitated wide-ranging opportunities for reflective practice, with an observed increased appreciation for complexity in Psychiatry. There was apparent tension between controlling content and facilitating the form of group process. Nonetheless, the structure appeared more approachable for medical students and those early in training.

scientific communication and education↗

bioRxiv2022

Characterization of prefusion-F-specific antibodies elicited by natural infection with human metapneumovirus

Human metapneumovirus (hMPV) is a major cause of acute respiratory tract infections in infants and the elderly for which there are no approved vaccines or antibody therapies. The viral fusion (F) glycoprotein is required for entry and is the primary target of neutralizing antibodies, however, little is known about the humoral immune response generated by humans as a result of natural infection. Here, we use stabilized hMPV F proteins to interrogate memory B cells from two elderly donors. We obtained over 700 paired non-IgM antibody sequences representing 563 clonotypes, indicative of a highly polyclonal antibody response to hMPV F in these individuals. Characterization of 136 of these monoclonal antibodies revealed broad recognition of the hMPV F surface, with potent neutralizing antibodies targeting each antigenic site. Cryo-EM structures of two neutralizing antibodies reveal the molecular basis for recognition of two prefusion-specific epitopes at the membrane-distal apex of hMPV F. Collectively these results provide new insights into the humoral response to hMPV infection in the elderly and will guide development of novel vaccine antigens.

immunology↗

bioRxiv2020

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human {gamma}-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a novel approach to effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.

microbiology↗