Zn2+ acts as a brake signal for axonal transport by directly inhibiting motor protein progression

Accurate delivery of cargo over long distances through axonal transport requires precise spatiotemporal regulation. Here we discover that Zn2+, either released from lysosomes through TRPML1 or influx via depolarization, inhibits axonal transport. Zn2+-mediated inhibition is neither selective for cargo nor for cell type because elevated Zn2+ (IC50 ≈ 5 nM) reduces both lysosomal and mitochondrial motility in primary rat hippocampal neurons and HeLa cells. We further reveal that Zn2+ directly binds to microtubules and inhibits movement of kinesin motors. Loss of TRPML1 function, which causes Mucolipidosis Type IV (MLIV) disease, impairs lysosomal Zn2+ release, disrupts Zn2+-mediated regulation of axonal transport, and increases overall organellar motility. In addition, MLIV patient mutations in TRPML1 have decreased Zn2+ permeability, which parallels disease severity. Our results reveal that Zn2+ acts as a critical signal to locally pause axonal transport by directly blocking the progression of motor proteins on microtubules.Significance StatementDisruptions in proper axonal transport have been linked to neurodevelopmental and neurodegenerative diseases. Here we discover that activation of the lysosomal channel TRPML1 arrests lysosomal trafficking. Such lysosome self-regulation mechanism is mediated via TRPML1-mediated Zn2+, not Ca2+. We further reveal that Zn2+ acts as a critical brake signal to pause axonal transport locally by directly decorating microtubules and blocking the movement of motor proteins. Dysfunction of TRPML1, the genetic cause of Mucolipidosis type IV (MLIV), blocks lysosomal Zn2+ release, causing loss of fine-tuning of lysosomal motility. Overall, this study implicates the importance of Zn2+ signals and axonal transport in the pathology of MLIV and reveals new signaling roles for Zn2+ in regulating cell processes involved with microtubule-based transport.

RHO GTPase-Related Long Noncoding RNAs in Human Cancers

RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.

Understanding a Mechanistic Basis of ABA Involvement in Plant Adaptation to Soil Flooding: The Current Standing

Soil flooding severely impairs agricultural crop production. Plants can cope with flooding conditions by embracing an orchestrated set of morphological adaptations and physiological adjustments that are regulated by the elaborated hormonal signaling network. The most prominent of these hormones is ethylene, which has been firmly established as a critical signal in flooding tolerance. ABA (abscisic acid) is also known as a “stress hormone” that modulates various responses to abiotic stresses; however, its role in flooding tolerance remains much less established. Here, we discuss the progress made in the elucidation of morphological adaptations regulated by ABA and its crosstalk with other phytohormones under flooding conditions in model plants and agriculturally important crops.

PET Imaging Radiotracers of Chemokine Receptors

Chemokines and chemokine receptors have been recognized as critical signal components that maintain the physiological functions of various cells, particularly the immune cells. The signals of chemokines/chemokine receptors guide various leukocytes to respond to inflammatory reactions and infectious agents. Many chemokine receptors play supportive roles in the differentiation, proliferation, angiogenesis, and metastasis of diverse tumor cells. In addition, the signaling functions of a few chemokine receptors are associated with cardiac, pulmonary, and brain disorders. Over the years, numerous promising molecules ranging from small molecules to short peptides and antibodies have been developed to study the role of chemokine receptors in healthy states and diseased states. These drug-like candidates are in turn exploited as radiolabeled probes for the imaging of chemokine receptors using noninvasive in vivo imaging, such as positron emission tomography (PET). Recent advances in the development of radiotracers for various chemokine receptors, particularly of CXCR4, CCR2, and CCR5, shed new light on chemokine-related cancer and cardiovascular research and the subsequent drug development. Here, we present the recent progress in PET radiotracer development for imaging of various chemokine receptors.

Clinical Applications and Properties of Calcium Citrate Malate

This article is an examination of the Clinical applications and properties of Calcium Citrate Malate. The scientific development and subsequent need to understand the properties of Calcium Citrate Malate, that make it an excellent candidate for treatment of disorders in various clinical domains, continues to influence the researchers all over the globe today. This article examines the research done and published by researchers and scientists. Consideration of current trends and data in scientific queries and demonstrates further aspects of the clinical applications and properties of Calcium Citrate Malate. Additionally, this article explores options for the role of Calcium Citrate Malate supplementation in dental care, to prevent tooth loss, erosion and abrasion, in Immunology as a critical signal for inflammation, in joints to treat osteoarthritis and in nephrology to tackle the renal stone problem.

Dexmedetomidine reduces isoflurane-induced neuroapoptosis through regulating BDNF and proBDNF

Background: It is well-acknowledged that Isoflurane induces neuroapoptosis in neonatal rats. Dexmedetomidine, as an α2-adrenergic agonist, was previously demonstrated to provide neuroprotection when administered during isoflurane anesthesia. Our study aims to investigate the mechanisms concerning the neuroprotective effect of dexmedetomidine from the alterations of BDNF,ERK, and JNK signals in the hippocampal region. Methods: Neonatal Sprague-Dawley rats at postnatal day 7 were assigned into Control group, Isoflurane group, Dexmedetomidine group and Inhibitor group. After exposed to 2% isoflurane in 40% of oxygen mixed with nitrogen for 4h, the hippocampus tissues were separated and critical signal pathway proteins of BDNF, proBDNF, JNK, ERK, and caspase 3 were detected. Results: Neuroapoptosis was triggered by Isoflurane with the increased expression of caspase 3 and TUNEL-positive cells. This effect was reversed by dexmedetomidine accompanying with up-regulation of BDNF and phospho-ERK and down-regulation of proBDNF and phospho-JNK. Conclusions: This study revealed that dexmedetomidine pretreatment can attenuate neurotoxicity caused by isoflurane in neonatal rats by regulating BDNF, proBDcNF, ERK, and JNK, which would provide a new target for neuroprotection.

Pesticide Exposure During Development Does Not Affect the Larval Pheromones, Feeding Rates, or Morphology of Adult Honey Bee (Apis mellifera) Queens

Recent work demonstrated that honey bee (Apis mellifera L.) queens reared in pesticide-laden beeswax exhibit significant changes in the composition of the chemicals produced by their mandibular glands including those that comprise queen mandibular pheromone, which is a critical signal used in mating as well as queen tending behavior. For the present study, we hypothesized that pesticide exposure during development would alter other queen-produced chemicals, including brood pheromone in immature queens, thus resulting in differential feeding of queen larvae by nurse workers, ultimately impacting adult queen morphology. We tested these hypotheses by rearing queens in beeswax containing field-relevant concentrations of (1) a combination of tau-fluvalinate and coumaphos, (2) amitraz, or (3) a combination of chlorothalonil and chlorpyrifos. These pesticides are ubiquitous in most commercial beekeeping operations in North America. We observed nurse feeding rates of queen larvae grafted into pesticide-laden beeswax, analyzed the chemical composition of larval queen pheromones and measured morphological markers in adult queens. Neither the nurse feeding rates, nor the chemical profiles of immature queen pheromones, differed significantly between queens reared in pesticide-laden wax compared to queens reared in pesticide-free wax. Moreover, pesticide exposure during development did not cause virgin or mated adult queens to exhibit differences in morphological markers (i.e., body weight, head width, or thorax width). These results were unexpected given our previous research and indicate that future work is needed to fully understand how pesticide exposure during development affects honey bee queen physiology, as well as how various adult queen quality metrics relate to each other.

Controllable multichannel acousto-optic modulator and frequency synthesizer enabled by nonlinear MEMS resonator

Nonlinear physics-based harmonic generators and modulators are critical signal processing technologies for optical and electrical communication. However, most optical modulators lack multi-channel functionality while frequency synthesizers have deficient control of output tones, and they additionally require vacuum, complicated setup, and high-power configurations. Here, we report a piezoelectrically actuated nonlinear Microelectromechanical System (MEMS) based Single-Input-Multiple-Output multi-domain signal processing unit that can simultaneously generate programmable parallel information channels (> 100) in both frequency and spatial domain. This significant number is achieved through the combined electromechanical and material nonlinearity of the Lead Zirconate Titanate thin film while still operating the device in an ambient environment at Complementary-Metal–Oxide–Semiconductor compatible voltages. By electrically detuning the operation point along the nonlinear regime of the resonator, the number of electrical and light-matter interaction signals generated based on higher-order non-Eigen modes can be controlled meticulously. This tunable multichannel generation enabled microdevice is a potential candidate for a wide variety of applications ranging from Radio Frequency communication to quantum photonics with an attractive MEMS-photonics monolithic integration ability.

Determination by Relaxation Tests of the Mechanical Properties of Soft Polyacrylamide Gels Made for Mechanobiology Studies

Following the general aim of recapitulating the native mechanical properties of tissues and organs in vitro, the field of materials science and engineering has benefited from recent progress in developing compliant substrates with physical and chemical properties similar to those of biological materials. In particular, in the field of mechanobiology, soft hydrogels can now reproduce the precise range of stiffnesses of healthy and pathological tissues to study the mechanisms behind cell responses to mechanics. However, it was shown that biological tissues are not only elastic but also relax at different timescales. Cells can, indeed, perceive this dissipation and actually need it because it is a critical signal integrated with other signals to define adhesion, spreading and even more complicated functions. The mechanical characterization of hydrogels used in mechanobiology is, however, commonly limited to the elastic stiffness (Young’s modulus) and this value is known to depend greatly on the measurement conditions that are rarely reported in great detail. Here, we report that a simple relaxation test performed under well-defined conditions can provide all the necessary information for characterizing soft materials mechanically, by fitting the dissipation behavior with a generalized Maxwell model (GMM). The simple method was validated using soft polyacrylamide hydrogels and proved to be very useful to readily unveil precise mechanical properties of gels that cells can sense and offer a set of characteristic values that can be compared with what is typically reported from microindentation tests.