Biology subjects

Low, D.

Publications and source records attributed to Low, D..

6 recordsLinked to original sources

bioRxiv2026

Roles of bacterial growth competition systems in colonization of the murine gut

The gut microbiome is essential for human health. Although the gut microbiota is largely stable at the species level in healthy individuals, strain-level variation remains less understood. Many bacterial strains encode toxin delivery systems that may shape competition within the gut. Here, we investigate how contact-dependent growth inhibition (CDI) and colicins influence intestinal colonization by a competitive murine Escherichia coli isolate, R12. We show that R12 can colonize an intact mouse gut microbiota by displacing resident Enterobacteriaceae, but success depends on multiple interacting factors. CDI systems and colicins provide a competitive advantage against resident E. coli, particularly during early colonization, while metabolic flexibility and access to alternative carbon sources support long-term persistence. Colonization outcomes vary between hosts and are shaped by resident microbiota composition, strain-level competition, and the initial invader-to-resident ratio. Overall, successful gut invasion is determined by the combined effects of bacterial antagonistic systems, metabolic capacity, and ecological context.

microbiology↗

bioRxiv2023

Paradoxical activation of a type VI secretion system (T6SS) phospholipase effector by its cognate immunity protein

Type VI secretion systems (T6SS) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt the tli immunity gene of Enterobacter cloacae and induce auto-permeabilization through unopposed activity of the Tle phospholipase effector. This hyper-permeability phenotype is T6SS-dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion of tli does not induce hyper-permeability because {Delta}tli null mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of the tli lipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyper-permeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli-dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG {beta}-spike protein. Together, these findings indicate that Tli has distinct functions depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export.

microbiology↗

bioRxiv2020

HNRNPM controls circRNA biogenesis and splicing fidelity to sustain prostate cancer cell fitness

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.

genomics↗

bioRxiv2019

Radiologic Evaluation of the Influence of Cleft Type on Nasal Dorsum Growth

PurposeThe study was designed to evaluate whether intrinsic morphological characteristics of the nasal dorsum are affected by cleft type, specifically cleft lip only (CL) and cleft lip with cleft palate(CL/P).\n\nMethods576 cleft patients (278 CL only, 298 CL/P), and 333 individuals without orofacial clefts were retrospectively enrolled. Lateral cephalometric radiographs of all individuals were taken to evaluate the nasal length and nasal dorsum height. Dunns test was used to analyze the difference (p < 0.001).\n\nResultsIn CL and control, the angulation of the nasal bone and nasal dorsum increase by age similarly (5y-18y, p>0.05). In CL, the total dorsal length is significantly shorter (5y-18y, p<0.001). Although the upper nasal dorsum is similar (except in 5y-6y), the lower nasal dorsum is shorter (5y-18y, p<0.001).\n\nIn CLP, there is no significant difference in the nasal bone angle compared with controls between 5y-7y. However, it develops insufficiently as children grow (8y-18y, p<0.001). The nasal dorsum angle is notably smaller (5y-18y, p<0.001). Nasal bone length is not significantly different from control at all stages except during ages 11y-13y (p<0.05). Total nasal dorsal length is similar to the control at skeletal maturity (17y-18y, p>0.05), although it is shorter during 8y to 16y (p<0.05). The upper nasal dorsum is overdeveloped (14y-18y, p<0.05), whereas the lower nasal dorsum is underdeveloped (5y-18y, p<0.001).\n\nConclusionCL inhibits the growth of nasal dorsum length, leading to short nose deformity. CL/P patients are prone to saddle-nose deformity because of the diminished nasal height (decreased nasal angle).

developmental biology↗

bioRxiv2019

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

The etiology of neurodevelopmental disorders is linked to defects in Parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia, have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a novel framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.

neuroscience↗

bioRxiv2018

Manipulation of microbiota reveals altered myelination and white matter plasticity in a model of Huntington disease

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.

neuroscience↗