Capturing resting T cells: the perils of PLL.
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ABSTRACT:
SUBMITTER: Santos AM
PROVIDER: S-EPMC7612954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although crystal structures of various voltage-gated K(+) (Kv) and Na(+) channels have provided substantial information on the activated conformation of the voltage-sensing domain (VSD), the topology of the VSD in its resting conformation remains highly debated. Numerous studies have investigated the VSD resting state in the Kv Shaker channel; however, few studies have explored this issue in other Kv channels. Here, we investigated the VSD resting state of KCNQ2, a K(+) channel subunit belonging to the KCNQ (Kv7) subfamily of Kv channels. KCNQ2 can coassemble with the KCNQ3 subunit to mediate the IM current that regulates neuronal excitability. In humans, mutations in KCNQ2 are associated with benign neonatal forms of epilepsy or with severe epileptic encephalopathy. We introduced cysteine mutations into the S4 transmembrane segment of the KCNQ2 VSD and determined that external application of Cd(2+) profoundly reduced the current amplitude of S4 cysteine mutants S195C, R198C, and R201C. Based on reactivity with the externally accessible endogenous cysteine C106 in S1, we infer that each of the above S4 cysteine mutants forms Cd(2+) bridges to stabilize a channel closed state. Disulfide bonds and metal bridges constrain the S4 residues S195, R198, and R201 near C106 in S1 in the resting state, and experiments using concatenated tetrameric constructs indicate that this occurs within the same VSD. KCNQ2 structural models suggest that three distinct resting channel states have been captured by the formation of different S4-S1 Cd(2+) bridges. Collectively, this work reveals that residue C106 in S1 can be very close to several N-terminal S4 residues for stabilizing different KCNQ2 resting conformations.
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Project description:Mesenchymal stem cells (MSCs) are highly important in biomedicine and hold great potential in clinical treatment for various diseases. In recent years, the capabilities of MSCs have been under extensive investigation for practical application. Regarding therapy, the efficacy usually depends on the amount of MSCs. Nevertheless, the yield of MSCs is still limited due to the traditional cultural methods. Herein, we proposed a three-dimensional (3D) scaffold prepared using poly lactic-co-glycolic acid (PLGA) nanofiber with polylysine (PLL) grafting, to promote the growth and proliferation of MSCs derived from the human umbilical cord (hUC-MSCs). We found that the inoculated hUC-MSCs adhered efficiently to the PLGA scaffold with good affinity, fast growth rate, and good multipotency. The harvested cells were ideally distributed on the scaffold and we were able to gain a larger yield than the traditional culturing methods under the same condition. Thus, our cell seeding with a 3D scaffold could serve as a promising strategy for cell proliferation in the large-scale production of MSCs. Moreover, the simplicity and low preparation cost allow this 3D scaffold to extend its potential application beyond cell culture.Graphical abstractSupplementary informationThe online version contains supplementary material available at 10.1186/s40643-023-00635-6.
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Project description:BackgroundMatching animal movement with the behaviors that shape life history requires a rigorous connection between the observed patterns of space use and inferred behavioral states. As animal-borne dataloggers capture a greater diversity and frequency of three dimensional movements, we can increase the complexity of movement models describing animal behavior. One challenge in combining data streams is the different spatial and temporal frequency of observations. Nested movement models provide a flexible framework for gleaning data from long-duration, but temporally sparse, data sources.ResultsUsing a two-layer nested model, we combined geographic and vertical movement to infer traveling, foraging and resting behaviors of Humpback whales off the West Antarctic Peninsula. This approach refined previous work using only geographic data to delineate coarser behavioral states. Our results showed increased intensity in foraging activity in late season animals as the whales prepared to migrate north to tropical calving grounds. Our model also suggests strong diel variation in movement states, likely linked to daily changes in prey distribution.ConclusionsUsing a combination of two-dimensional and three-dimensional movement data, we highlight the connection between whale movement and krill availability, as well as the complex spatial pattern of whale foraging in productive polar waters.
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Project description:Advances in understanding the ways in which the immune system fails to control tumor growth or prevent autoimmunity have led to the development of powerful therapeutic strategies to treat these diseases. In contrast to conventional therapies that have a broadly suppressive effect, immunotherapies are more akin to targeted therapies because they are mechanistically driven and are typically developed with the goal of "drugging" a specific underlying pathway or phenotype. This means that their effects and toxicities are, at least in theory, more straightforward to anticipate. The development of functionalized antibodies, genetically engineered T cells, and immune checkpoint inhibitors continues to accelerate, illuminating new biology and bringing new treatment to patients. In the following sections, we provide an overview of immunotherapeutic concepts, highlight recent advances in the field of immunotherapies, and discuss controversies and future directions, particularly as these pertain to hematologic oncology or blood-related diseases. We conclude by illustrating how original research published in this journal fits into and contributes to the overall framework of advances in immunotherapy.
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Project description:Purpose of reviewT cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumab-based induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies.Recent findingsAlemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CAR-T cell therapy are at the stage of pre-clinical assessments of activity and feasibility. The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-in-human results in T-PLL, and urgently have to be transferred to systematic clinical testing.
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