Biology subjects

Li, X.-L.

Publications and source records attributed to Li, X.-L..

5 recordsLinked to original sources

bioRxiv2023

Wall-following: phylogenetic context of an enhanced behaviour in stygomorphic Sinocyclocheilus (Cypriniformes: Cyprinidae) cavefishes

With 75 known species, the freshwater-fish genus Sinocyclocheilus is the largest cavefish radiation in the world, emerging as a model system for evolutionary studies. They show multiple adaptations for cave dwelling (stygomorphic adaptations), which include a range of traits such as eye degeneration (Normal-eyed, Micro-eyed and Eyeless), depigmentation of skin, and in some species, the presence of "horns". Their behavioural adaptations to subterranean environments, however, are poorly understood. Wall-following (WF) behaviour, where an organism remains in close contact with the boundary demarcating its habitat when in the dark, is a peculiar behaviour observed in a wide range of animals and is enhanced in some cave dwellers. Hence, we hypothesize wall-following to be present also in Sinocyclocheilus, possibly enhanced in Eyeless species compared to species with visual cues (Normal / Micro-eyed species). Using 13 species representative of Sinocyclocheilus radiation and eye-morphs, we designed a series of assays, based on pre-existing methods for Astyanax mexicanus behavioural experiments, to examine wall-following behaviour under three stimulation conditions. Our results indicate that eyeless species exhibit significantly enhanced levels of WF compared to Normal-eyed species, with Micro-eyed forms demonstrating intermediate levels. Using a mtDNA based dated phylogeny (chronogram with four clades A - D), we traced the degree of WF of these forms to outline common patterns. We show that intensity of WF behaviour is high in the subterranean clades (B & C) compared to clades with free-living species (A & D). Experiments on WF behaviour revealed that eyeless species are highly sensitive to vibrations, whereas normal-eyed species are the least sensitive. Since WF behaviour is present to some degree in all Sinocyclocheilus species, and given that these fishes evolved in the late Miocene, we identify this behaviour as being ancestral with WF enhancement related to cave occupation. Our results from this diversification-scale study of cavefish behaviour suggest that enhanced wall-following behaviour may be a convergent trait across all stygomorphic cavefish lineages. Significance statementSinocyclocheilus, a genus of 75 species of freshwater cavefish, is an emerging model system in evolutionary studies. Their adaptations for subterranean life, including eye degeneration, skin depigmentation, and horn-like structures, are well-known, but their behavioural adaptations remain understudied. Here we focus on a phenomenon, called "wall-following," where fish stay close to the cave walls in absence of light. We hypothesized that this behaviour would be more pronounced in eyeless species. We selected 13 species, representative of the diversity of the genus and eye types, and observed their wall-following behaviour under different conditions. Results were intriguing; eyeless species exhibited heightened wall-following behaviour compared to their sighted counterparts, with small-eyed species falling in between. Researchers also mapped this behaviour on a phylogenetic tree, discovering a pattern: cave-dwelling clades showed stronger wall-following than free-living ones. Wall-following is prevalent in all Sinocyclocheilus species and, given the evolutionary history of the genus, is considered an ancestral behaviour that intensified with cave adaptation. These findings contribute to our understanding of convergent evolution, suggesting that enhanced wall-following may be a shared trait among diverse cavefish lineages.

animal behavior and cognition↗

bioRxiv2023

Ultralow background membrane editors for spatiotemporal control of lipid metabolism and signaling

Phosphatidic acid (PA) is a multifunctional lipid with important metabolic and signaling functions, and efforts to dissect its pleiotropy demand strategies for perturbing its levels with spatiotemporal precision. Previous membrane editing approaches for generating local PA pools used light-mediated induced proximity to recruit a PA-synthesizing enzyme, phospholipase D (PLD), from the cytosol to the target organelle membrane. Whereas these optogenetic PLDs exhibited high activity, their residual activity in the dark led to undesired chronic lipid production. Here, we report ultralow background membrane editors for PA wherein light directly controls PLD catalytic activity, as opposed to localization and access to substrates, exploiting a LOV domain-based conformational photoswitch inserted into the PLD sequence and enabling their stable and non-perturbative targeting to multiple organelle membranes. By coupling organelle-targeted LOVPLD activation to lipidomics analysis, we discovered different rates of metabolism for PA and its downstream products depending on the subcellular location of PA production. We also elucidated signaling roles for PA pools on different membranes in conferring local activation of AMP-activated protein kinase signaling. This work illustrates how membrane editors featuring acute, optogenetic conformational switches can provide new insights into organelle-selective lipid metabolic and signaling pathways. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/555787v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@7d2ec0org.highwire.dtl.DTLVardef@88418dorg.highwire.dtl.DTLVardef@187abf3org.highwire.dtl.DTLVardef@29f4d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2020

BBB pathophysiology independent delivery of siRNA in traumatic brain injury

Small interfering RNA (siRNA) represents a powerful strategy to mitigate the long-term sequelae of traumatic brain injury (TBI). However, poor permeability of siRNA across the blood brain barrier (BBB) poses a major hurdle. One approach to overcome this challenge involves treatment administration while the BBB is physically breached post-injury. However, this approach is only applicable to a subset of injuries with substantial BBB breach and can lead to variable therapeutic response due to the heterogeneity of physical breaching of BBB in TBI. Moreover, since physical breaching of BBB is transient, this approach offers a limited window for therapeutic intervention, which is not ideal as repeated dosing beyond the transient window of physically breached BBB might be required. Herein, we report a nanoparticle platform for BBB pathophysiology-independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density, which maximized the active transport of nanoparticles across BBB. Intravenous injection of engineered nanoparticles, within or outside the window of physically breached BBB in TBI mice resulted in 3-fold higher brain accumulation compared to conventional PEGylated nanoparticles and demonstrated up to 50% gene silencing. To our knowledge, this is the first reported example of BBB pathophysiology-independent drug delivery in TBI, and the first time combined modulation of surface chemistry and coating density has been shown to tune BBB penetration of nanoparticles. Taken together, our approach offers a clinically relevant approach to develop siRNA therapeutics for preventing long-term effects of TBI and deserves further exploration.Competing Interest StatementJMK has been a paid consultant and or equity holder for multiple biotechnology companies (listed here https://www.karplab.net/team/jeff-karp). The interests of JMK were reviewed and are subject to a management plan overseen by his institutions in accordance with its conflict of interest policies. N.J., J.MK., W.L., R.M., J.Q. and R.L. have one unpublished patent based on the nanoparticle work presented in this manuscript. For a list of entities with which R.L. is involved, compensated or uncompensated, see www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0.View Full Text

bioengineering↗

bioRxiv2020

Cabozantinib unlocks efficient in vivo targeted delivery of neutrophil-loaded nanoparticles into murine prostate tumors

A major barrier to the successful application of nanotechnology for cancer treatment is the efficient delivery of therapeutic payloads to metastatic tumor deposits. We have previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anti-cancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of bovine serum albumin (BSA)-coated polymeric nanoparticles (NPs) into murine PTEN/p53-deficient prostate tumors. Based on the observation that BSA-coating of NPs enhanced association and internalization by activated neutrophils in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pre-treated with cabozantinib. Flow cytometric analysis revealed a 4-fold increase of neutrophil-associated NPs within the tumor microenvironment (TME) of mice pre-treated with cabozantinib relative to untreated controls. At steady-state, following 3 days of cabozantinib/NP administration, 1% of systemically injected dye-loaded NPs selectively accumulated within the TME of mice that were pre-treated with cabozantinib, compared to 0.11% uptake for mice that did not receive cabozantinib pre-treatment. Strikingly, neutrophil depletion with Ly6G antibody abolished NP accumulation in tumors to baseline levels, demonstrating targeted neutrophil-mediated NP delivery to the prostate TME. In summary, we have discovered a novel nano-immunotherapeutic strategy for enhanced intratumoral delivery of injected NPs, which results in significantly higher NP accumulation than reported strategies in the nanotechnology literature to-date.

cancer biology↗

bioRxiv2018

Genetic Diversity and Coexistence of Babesia in Ticks (Acari: Ixodidae) from Northeastern

BackgroundBabesiosis is an emerging zoonosis in humans with significant and increasing health burden in China. A few systematic reports on Babesia spp. was involved with ticks, especially in the human babesiosis endemic areas.\n\nMethodsThe ticks were collected from 30 individual waypoints along 2.0 km transects in two recreational forested areas in Northeastern China. Then we screened them for Babesia spp. infection by amplifying the partial 18s rRNA gene with subsequent sequencing. Multivariate logistic regression analysis was used to access the association between infections and some related risk factors. The cluster analyses were performed using SaTScan v6.0 Software for identifying the geographic cluster of the positive samples in ticks from each waypoint.\n\nResultsA total of Ixodes persulcatus (n=2380) and Haemaphysalis concinna (n=461) ticks were collected. The 0.97% of I. persulcatus ticks were infected with five Babesia species, including B. bigemina (n=6), B. divergens (n=2), B. microti (n=3), B. venatorum (n=11) and one novel strain HLJ-8. Thirteen (2.92%) H.concinna ticks contained B. bigemina (n=1), B. divergens (n=1), three genetic variants of Babesia represented by HLJ-874 which was closely related to Babesia sp.MA#361-1, and eight other Babesia variants represented by HLJ242 which were similar to B.crassa. Each study site had 5~6 different Babesia spp. One waypoint was more likely to yield B.venatorum (relative risk=15.36, P=0.045) than all other waypoints.\n\nConclusionsThere exists a high genetic diversity of Babesia spp. across a relatively small sampled region. Further study is needed to understand the risks these variants pose for human health.\n\nAuthor SummaryBabesiosis is the subject of increasing interest as an emerging zoonosis in humans with significant and increasing health burden of the disease at recently. In China, many probably human babesiosis cases who had a history of recent tick bite were found in Lyme endemic area in Northeastern China, where the prevalence of Babesia parasite in the ticks still was far underestimated. In the present study, we conducted a field survey for ticks to identify diversities and complexity of babesia, and then to assess the risk of human babesiosis, by means of a three years longitudinal study that mapped the location of the ticks tested positive for Babesia spp. at two forestry areas with a heavy burden of tick-borne pathogens. We firstly presented the prevalence of Babesia spp. especially the genetic diversities and coexistence of seven Babesia spp. including 2 novel species or variants at one small scale \"natural foci\" in northeastern China. This work is useful to understand the complexity of Babesia pathogen in China, and how the Babesia perpetuates over the long term in the environment, as well as potential risks for human health.

epidemiology↗