New Findings
What is the central question of this study?
We investigated the effects of intrathecal administration of a novel toxin, CTK 01512‐2, in a mouse model of Huntington's disease. We asked ...whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high‐risk brain intervention.
What is the main finding and its importance?
We provided evidence of a novel, local, neuroprotective effect of CTK 01512‐2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain.
Phα1β is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512‐2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512‐2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512‐2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512‐2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512‐2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512‐2 significantly improved motor performance in the open field task. CTK 01512‐2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512‐2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase‐3 in the spinal cord. CTK 01512‐2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512‐2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.
Protecting secret messages from being hacked is a vital problem. This research paper will present a simple and flexible data cryptography method. The method can encrypt-decrypt messages of any ...length. Also, it can be easily used to encrypt-decrypt gray and color images. The proposed method will use a private key, which contains the needed information to generate chaotic keys; these keys will be used to obtain indices keys, which will be used as a lockup table in the encryption and decryption phases. The generated key will be very sensitive to the P.K. contents. The P.K. used in the proposed method will have a complex structure, providing a huge key space that can resist attacks. The proposed method will be implemented using various messages, the obtained results will be analyzed, and several test analysis methods will be used to prove the achievements of the proposed method. The quality analysis will use the calculated values of MSE, PSNR, CC, and NSCR to prove the quality of the proposed method in both the encryption and decryption phases. A sensitivity analysis will be performed to show how the encryption and decryption phase is sensitive to the selected P.K.; any changes in the P.K. during the decryption phase will be considered a hacking attempt by producing a damaged decrypted message. A speed analysis will be provided to prove that the proposed method is efficient, and the obtained results will be compared with other methods' results to show the speedup provided by the proposed method.
The purpose of this research was to explore the integrative effects of tillage rotary tillage (RT), subsoiling tillage (SST), and no-tillage (NT) and nitrogen (N) fertilizer rate (N2, 200 kg N ha−1; ...N3, 300 kg N ha−1) on net photosynthetic rate (Pn), hormonal changes in grains, grain filling parameters, grain yield components, and grain yield of maize (Zea mays L.). The relationship among the yield components and grain filling parameter was also investigated. The results indicated that, on the average, tillage had no significant effect on maize yield under either N2 or N3, N rate had no significant effect on maize yield under RT and NT, only under SST, N3 increased maize grain yield significantly over N2 by 10.79%. Further on, SST with N3 enhanced Pn and promoted dry matter accumulation. The content of indole-3-acetic acid (IAA) and cytokinin (CTK) maintained a higher level over time under the SST with N3 compared with other treatments, gibberellic acid (GA) under SST with N3 had the lowest content from 21 to 28 DAP in two years. The grain filling parameter showed that SST with N3 promoted average grain filling rate and increased the weight of gradual increase period, rapid increase period, and slight increase period. It is concluded that the no-tillage with 200 kg N ha−1 is the suitable tillage as it saves tillage input, but subsoiling tillage had the advantage under 300 kg N ha−1, which improved photosynthetic rate, promoted dry matter accumulation and transport, optimized the balance of hormones, subsequently ameliorated the grain filling process, thus promoting kernels weight and ultimately increased yield.
•Maize yield response to tillage and nitrogen rate was mainly due to kernels weight difference in the Loess Plateau.•Subsoiling tillage with 300 kg N ha−1 optimized hormones and grain filling, resulting in increased kernels weight.•Under 200 kg N ha−1, no-tillage is the suitable practice as it saves tillage input without yield penalty.
•The embryogenic callus was mostly induced from the adaxial side of the explants.•Transcriptomic revealed differences between embryogenic and non-embryogenic callus.•IAA and CTK play a pivotal role ...in dedifferentiation and redifferentiation of cells.
Somatic embryogenesis system was an ideal one for the genetic transformation and propagation in vitro because it propagates efficiently, quickly and stably. The mechanism of the origin of somatic embryogenesis especially in cucumber has not been well illustrated since it is explored. The embryogenic callus was observed to be induced from the adaxial side and the non-embryogenic callus were induced from the abaxial side of the cucumber cotyledon nodes, and then the embryos generated from the embryogenic callus but not from the non-embryogenic callus. The histology and transcriptomic analysis were performed to probe the dedifferentiation and redifferentiation difference between the adaxial side and the abaxial side of the cucumber cotyledon nodes. It showed that embryogenic callus having dense cytoplasm, clear nucleus and regular shaped cells was induced from the adaxial side of the cotyledon node and the non-embryogenic callus with unclear border of nucleus and irregular shaped cells were generated from the abaxial side. A total of 5838 differentially expressed genes (DEGs) were screened between embryogenic and non-embryogenic callus, which were highly enriched in auxin and CTK synthesis and signaling pathways and substance metabolism pathway such as starch and amino acid in embryogenic callus. The IPA (Indole-3-pyruvic acid) genes, AUX1 (Auxin 1) genes and IPT (Isopentenyl transferase) genes involved in auxin and CTK biosynthesis and signaling pathways were up-regulated in embryogenic callus comparing with that in non-embryogenic callus. SS1 (starch synthase) genes related with starch synthesis, OATase (Ornithine acetyltransferase) genes related with arginine and proline synthesis were more highly induced in embryogenic callus than that in non-embryogenic callus. It will provide a reliable foundation for elucidating the difference between the origin of somatic embryogenesis during dedifferentiation and redifferentiation of cucumber cotyledon nodes.
The difficulties of evaluating patients with complex neuropsychiatric conditions and prescribing appropriate treatments are well known. Imaging complements clinical assessments and allows a clinician ...to narrow the differential diagnosis by facilitating accurate and efficient evaluation. This is particularly relevant to neuropsychiatric conditions that are often diagnosed using a trial-and error process of exclusion. Single Photon Emission Computed Tomography (SPECT) is a functional brain imaging procedure that allows practitioners to measure the functional changes of gray matter structures based on regional cerebral blood flow (rCBF). The accurate diagnosis and treatment selection in psychiatry is challenging due to complex cases and frequent comorbidities. However, such complex neuropsychiatric conditions are increasingly benefitting from new treatment approaches, in addition to established medications. Among these are combination transcranial magnetic stimulation with ketamine infusions (CTK), hyperbaric oxygen therapy (HBOT) and perispinal administration of etanercept (PSE). This article provides readers with six case study examples that demonstrate how brain SPECT imaging can be used, both as a diagnostic tool, and as a potential biomarker for monitoring and evaluating novel treatments for patients with complex neuropsychiatric conditions. Six patients were assessed in our clinic and baseline brain SPECT imagesTourettes and a long history of alcohol were visually compared with SPECT images collected after periods of treatment with CTK or HBOT followed by PSE. This retrospective review demonstrates the clinical utility of these novel treatments and describes how SPECT imaging can complement standard diagnostic assessments. A novel display technique for SPECT images is described and we argue that SPECT imaging can be used for monitoring biomarker for clinical change.
To describe an atypical case of acanthamoeba keratitis with positive in vivo confocal microscopy in a non-contact lens user who presented with signs and symptoms suggestive of central toxic ...keratopathy.
The patient presented with bilateral, though sequential, decreased visual acuity with mild pain. Examination showed stromal haze with corneal flattening and thinning without epithelial defects. Optical coherence tonometry of the right eye revealed an inverse dome-shaped appearance of the opacity and in-vivo confocal imaging showed double-walled cysts consistent with acanthamoeba. Corneal haze, stromal loss, resolved and visual acuity improved over time.
Acanthamoeba is a rare cause of infectious keratitis that is most often associated with contact lens wear in developed countries. Typically, it presents with a unilateral decrease in visual acuity, photophobia, watering, and pain that is out of proportion to slit lamp examination findings. However, many atypical presentations have been reported in the literature. Consequently, it may be misdiagnosed, especially early in the course of the disease. This delay in diagnosis can lead to progressive ulceration and visual impairment. In addition, cyst formation can make eradication with anti-amoebic treatment especially difficult.
Central toxic keratopathy is a non-inflammatory clinical syndrome of unknown etiology that is most often associated with excimer laser ablation, though other associated causes have been reported. It is characterized by a central or paracentral opacity with corneal stromal loss and resultant hyperopic shift. The opacification and stromal loss mostly resolve over the course of months with an improvement in visual acuity. This report may help physicians broaden their differential and correctly diagnose atypical presentations of amoebic infection.
Summary
Cucumber fruits that have tubercules and spines (trichomes) are known to possess a warty (Wty) phenotype. In this study, the tuberculate fruit gene Tu was identified by map‐based cloning, and ...was found to encode a transcription factor (TF) with a single C2H2 zinc finger domain. Tu was identified in all 38 Wty lines examined, and was completely absent from all 56 non‐warty (nWty) lines. Cucumber plants transgenic for Tu (TCP) revealed that Tu was required for the Wty fruit phenotype. Subcellular localization showed that the fusion protein GFP–Tu was localized mainly to the nucleus. Based on analyses of semi‐quantitative and quantitative reverse transcription polymerase chain reaction (RT‐PCR), and mRNA in situ hybridization, we found that Tu was expressed specifically in fruit spine cells during development of fruit tubercules. Moreover, cytokinin (CTK) content measurements and cytological observations in Wty and nWty fruits revealed that the Wty fruit phenotype correlated with high endogenous CTK concentrations. As a result of further analyses on the transcriptomic profile of the nWty fruit epidermis and TCP fruit warts, expression of CTK‐associated genes, and hormone content in nWty fruit epidermis, Wty fruit warts and epidermis, and TCP fruit warts and epidermis, we found that Tu probably promoted CTK biosynthesis in fruit warts. Here we show that Tu could not be expressed in the glabrous and tubercule‐free mutant line gl that contained Tu, this result that futher confirmed the epistatic effect of the trichome (spine) gene Gl over Tu. Taken together, these data led us to propose a genetic pathway for the Wty fruit trait that could guide future mechanistic studies.
Phα1β is a neurotoxin purified from spider venom that acts as a
high-voltage-activated (HVA) calcium channel blocker. This spider peptide has
shown a high selectivity for N-type HVA calcium channels ...(NVACC) and an
analgesic effect in several animal models of pain. Its activity was associated
with a reduction in calcium transients, glutamate release, and reactive oxygen
species production from the spinal cord tissue and dorsal ganglia root (DRG) in
rats and mice. It has been reported that intrathecal (i.t.) administration of
Phα1β to treat chronic pain reverted opioid tolerance with a safer profile than
ω
-conotoxin MVIIA, a highly selective NVACC blocker.
Following a recent development of recombinant Phα1β (CTK 01512-2), a new
molecular target, TRPA1, the structural arrangement of disulphide bridges, and
an effect on glial plasticity have been identified. CTK 01512-2 reproduced the
antinociceptive effects of the native toxin not only after the intrathecal but
also after the intravenous administration. Herein, we review the Phα1β
antinociceptive activity in the most relevant pain models and its mechanisms of
action, highlighting the impact of CTK 01512-2 synthesis and its potential for
multimodal analgesia.
•There is a cross-talk between polyamines (PAs) and phytohormones under drought and well-watered conditions.•The changes of endogenous PAs and phytohormones resulted in accelerated proline metabolism ...and elevated AsA–GSH cycle and relevant genes expression.•Other metabolites such as total phenols, flavonoid, cysteine and metallothionein (MT) were also elevated with significantly increased endogenous PAs content.•On the contrary, the deficiency in PAs weakened antioxidant defense and proline metabolism, inhibited MT genes expression leading to aggravation of drought-induced stress damage.
Cross-talk between polyamines (PAs) and phytohormones may be involved in the regulation of drought tolerance in plants. The objective of this study was to determine the effects of exogenous spermidine (Spd) and a Spd inhibitor, dimethylthiourea (DCHA), on drought responses of white clover (Trifolium repens). Metabolic, protein, and gene transcript levels were evaluated at leaf relative water content levels of 87% for non-stressed plants and 50% for drought-stressed plants. The exogenous application of Spd (0.05mM) significantly increased endogenous PAs content whereas DCHA generally reduced PAs content. Phytohormone responses to Spd application included an elevated gibberellic acid (GA) and indole-3-acetic acid (IAA) content under non-stressed condition, and an increased GA and cytokinin (CTK) content as well as decreased IAA content under water deficit condition. The increase in endogenous PAs had no significant effect on abscisic acid (ABA) accumulation under either water treatment. Spd treatment resulted in enhanced antioxidant defense via maintenance of greater antioxidant enzyme activities and transcript levels, especially ascorbic acid (AsA). Other metabolites such as total phenols, flavonoids, proline, metallothionein (MT), and cysteine (Cyt) were also elevated with Spd treatment. On the contrary, inhibition of Spd biosynthesis weakened antioxidant defense, decreased proline metabolism, and inhibited MT genes expression leading to aggravation of drought-induced stress damages. These results suggest that changes of PAs and phytohormones play critical roles in the improvement of drought tolerance in white clover, which are attributed to the alleviation of oxidative stress, inhibition of leaf senescence, and maintenance of growth under drought stress.
CTK 01512–2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the
Phoneutria nigriventer
spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and ...shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512–2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512–2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1–4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512–2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512–2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.
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