Biology subjects

Tang, M. M.

Publications and source records attributed to Tang, M. M..

3 recordsLinked to original sources

bioRxiv2022

Plantar flexor deficits following Achilles tendon rupture: a novel small animal dynamometer and detailed instructions

Plantar flexor functional deficits measured using joint dynamometry are associated with poor outcomes in patients following Achilles tendon rupture. In this study, we developed a small animal dynamometer to quantify functional deficits in a rat Achilles tendon rupture model. Like our reported plantar flexor deficits in patients recovering from Achilles tendon ruptures, we found in our small animal model functional deficits across the ankle range of motion, resulting in an average 34% less positive work being done compared to the uninjured contralateral limb. These functional deficits are similar to 38% less plantar flexor work done by patients who were treated non-surgically in our prior research. Further, these deficits were greater in plantar flexion than dorsiflexion, which agree with clinical complaints of limited function during tasks like jumping and hiking. These findings highlight the impact of muscle-tendon loading during early tendon healing on long-term plantar flexor function and serve as compelling evidence that our Sprague Dawley rat model of an Achilles tendon rupture recapitulates the human disease. We provide thorough documentation for other groups to build their own dynamometers, which can be modified to meet unique experimental criteria. SIGNIFIGANCEPreclinical models are critical tools for translating knowledge discovery to clinical decision making. We developed a low-cost and flexible joint dynamometer that quantifies joint function in small animals. Here, we used a rat model to test the implications of Achilles tendon ruptures not surgically repaired on plantar flexor function. We found that Achilles tendon ruptures in a rodent model closely resemble the functional deficits our group has observed in patients.

bioengineering↗

bioRxiv2021

Oligomerization-driven MLKL ubiquitylation antagonises necroptosis

Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor significance of this event have been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin insoluble cell fraction comprising plasma/organellar membranes and protein aggregates. This ubiquitylated form is diminished by a plasma membrane located deubiquitylating enzyme. MLKL is ubiquitylated on at least 4 separate lysine residues once oligomerized, and this correlates with proteasome- and lysosome-dependent turnover. Using a MLKL-DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licences MLKL auto-activity independent of necroptosis signalling in mouse and human cells. Therefore, besides its role in the kinetic regulation of MLKL-induced death following an exogenous necroptotic stimulus, ubiquitylation also contributes to the restraint of basal levels of activated MLKL to avoid errant cell death.

molecular biology↗

bioRxiv2018

GrgA as a potential target of selective antichlamydials

Chlamydia is a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rare Chlamydia variant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, the Chlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance in Chlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.

microbiology↗