Cargo transport along axons, a physiological process mediated by motor proteins, is essential for neuronal function and survival. A current limitation in the study of axonal transport is the lack of ...a robust imaging technique with a high spatiotemporal resolution to visualize and quantify the movement of motor proteins in real‐time and in different depth planes. Herein, we present a dynamic imaging technique that fully exploits the characteristics of upconversion nanoparticles. This technique can be used as a microscopic probe for the quantitative in situ tracking of retrograde transport neurons with single‐particle resolution in multilayered cultures. This study may provide a powerful tool to reveal dynamic neuronal activity and intra‐axonal transport function as well as any associated neurodegenerative diseases resulting from mutation or impairment in the axonal transport machinery.
Monitoring motoring: The real‐time monitoring of the movement of motor proteins by conventional fluorescence microscopy has significant limitations owing to the low penetration depth of light and complex instrumentation. To address these issues, upconversion microscopy was used for the real‐time visualization of dynein tracking in axons and multi‐layered cell cultures.
Even nowadays, the question of whether hypothermia can genuinely be considered therapeutic care for patients with traumatic spinal cord injury (SCI) remains unanswered. Although the mechanisms of ...hypothermia action are yet to be fully explored, early hypothermia for patients suffering from acute SCI has already been implemented in clinical settings. This article discusses measures for inducing various forms of hypothermia and summarizes several hypotheses describing the likelihood of hypothermia mechanisms of action. We present our objective neuro-electrophysiological results and demonstrate that early hypothermia manifests neuroprotective effects mainly during the first- and second-month post-SCI, depending on the severity of the injury, time of intervening, duration, degree, and modality of inducing hypothermia. Nevertheless, eventually, its beneficial effects gradually but consistently diminish. In addition, we report potential complications and side effects for the administration of general hypothermia with a unique referment to the local hypothermia. We also provide evidence that instead of considering early hypothermia post-SCI a therapeutic approach, it is more a neuroprotective strategy in acute and sub-acute phases of SCI that mostly delay, but not entirely avoid, the natural history of the pathophysiological events. Indeed, the most crucial rationale for inducing early hypothermia is to halt these devastating inflammatory and apoptotic events as early and as much as possible. This, in turn, creates a larger time-window of opportunity for physicians to formulate and administer a well-designed personalized treatment for patients suffering from acute traumatic SCI.
We developed the functionalized upconversion nanoprobe with ultrasensitive and responsive properties for glucose detection, the responsive emission and satisfactory differentiated performances are ...observed in situ and in vitro.
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•Ultrasensitive and rapid detection strategy of glucose was constructed based on lanthanide-doped upconversion nanoprobe.•The functionalized nanoprobe can distinguish cancer cells from normal cells by in vitro emission intensity via optical bioimaging.•The designed nanoprobe would facilely achieve glucose detection in situ and in vitro with ultralow detection limit.
Various approaches for detecting glucose concentration in real time are emerging at a breakneck pace. Glucose metabolism is closely linked to severe pathological events, which would either cause or predispose many progressive diseases in human. Herein, hydrophilic upconversion nanoprobes NaGdF4: Yb3+, Er3+@Ag anchored with glucose oxidase (GOx) for glucose detection with lower detection limits have been efficaciously constructed. In the upconversion nanoprobes, NaGdF4: Yb3+, Er3+ cores, and Ag layers act as energy donors and effective quenchers, respectively, through energy transfer. Moreover, the layer of Ag may disintegrate by H2O2 in the presence of glucose when glucose oxidase anchoring on the exterior of NaGdF4: Yb3+, Er3+@Ag nanoprobes, which leads to the phenomenon of upconverting emission recovery. Additionally, NaGdF4: Yb3+, Er3+@Ag-GOx has an ultralow detection limit of 1.77 μmol L−1 on glucose detection, and it can achieve optical bioimaging to distinguish cancer cells from normal cells. As a result, the NaGdF4: Yb3+, Er3+@Ag nanoprobes could be expanded to detect diverse H2O2-involved analytes. Overall, this nanoprobe has promising potential to be a compelling tool for the biomedical applications.
Electrophysiological analysis using somatosensory-evoked potentials (SEPs) and behavioral assessment using Basso, Beattie, Bresnahan (BBB) scale were compared over time for graded Multicenter Animal ...Spinal Cord Injury Study (MASCIS) contusion spinal cord injury (SCI).
To study the SEP responses across different contusion injury severities and to compare them with BBB scores.
For any SCI therapy evaluation, it is important to accurately and objectively standardize the injury model. The graded MASCIS contusion injuries on dorsal spine have been standardized using BBB, which is subjective and prone to human errors. Furthermore, dorsal pathway disruption does not always produce locomotor deficits. SEP monitoring provides an advantage of providing a reliable and objective assessment of the functional integrity of dorsal sensory pathways.
Four groups of Fischer rats received contusion at T8 using New York University (NYU)-MASCIS impactor from impact heights of 6.25 mm (mild), 12.5 mm (moderate), 25 mm (severe), or 50 mm (very severe). The control group underwent laminectomy only. SEP and BBB recordings were performed once before injury, and then weekly for up to 7 weeks.
Graded levels of injury produced concomitant attenuations in hindlimb SEP amplitudes. Following injury, 25 and 50 mm groups together differed significantly from 12.5 and 6.25 mm groups (P < 0.01). From week 5, differences between 12.5 and 6.25 mm groups also became apparent (P < 0.01), which showed significant electrophysiological improvement. However, no significant differences were observed between 25 and 50 mm groups, which showed negligible electrophysiological recovery. Although comparable differences between different groups were also detected by BBB after injury (P < 0.001), BBB was less sensitive in detecting any improvement in 6.25 and 12.5 mm groups.
SEP amplitudes and BBB scores decrease corresponding to increase in injury severity, however, these show different temporal patterns of recovery. These results demonstrate the utility of SEPs in conjunction with BBB, to monitor therapeutic interventions in SCI research.
Transplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies ...have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell-derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period.
hES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES-treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4).
hES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post-injury initially caused increased cell death but did not affect the long-term cell proliferation or survival, indicating that cells can be transplanted sooner than conventionally accepted.
Primary and secondary syphilis infections are on the rise. Between 2015 and 2016, cases in persons aged 65 and older increased by 50%. Anorectal infections are uncommon and have a varying clinical ...and endoscopic presentation, making diagnosis difficult. This is a case of rectal syphilis manifested as gastrointestinal (GI) bleeding, in the setting of neurosyphilis. A 73-year-old male with a history of prostate cancer status post radiation treatment complicated by radiation proctopathy was admitted for hematochezia. Prior to admission, the patient presented to ophthalmology for blurred vision. Based on the ophthalmologic exam and a positive reactive rapid plasma reagin (1:64), he was diagnosed with neurosyphilis. The patient later reported having unprotected receptive anal intercourse with multiple partners. A colonoscopy revealed multiple clean ulcers with surrounding erythema in the rectum, up to 15 cm from the anal verge, deemed to be the source of bleeding. Other notable findings included patchy areas of serpiginous vessels in the distal rectum consistent with radiation proctopathy. Targeted biopsies were collected around the ulcers. The pathology revealed submucosal perivascular cuffing with spirochete-like elements, which in the setting of positive RPR, were consistent with rectal syphilis. He was treated with two weeks of intravenous penicillin and GI bleeding resolved. A repeat flexible sigmoidoscopy two months after treatment showed no evidence of active ulcerations. While the incidence of syphilis is increasing, anorectal syphilis remains an uncommon presentation with a paucity of cases. Presenting symptoms and endoscopic findings of rectal syphilis appear to be variable and non-specific. Prior reports of rectal syphilis included rectal masses, mimicking cancer, or rectal ulcers, concerning for inflammatory bowel disease. In this case, radiation proctopathy was a confounding factor for the etiology of GI bleeding until the diagnosis of rectal syphilis was made. This case highlights a unique GI manifestation of syphilis in the setting of neurosyphilis, manifested as rectal ulcers.
•A new general equation for estimating the variation of linear retention indexes as a function of retention time tolerances has been derived.•New psychoactive substances and traditional drugs ...properly identified by their linear retention index and GC/MS.•A retention index master list avoids the need for analytical chemical standards.•Column polarity is the only relevant factor as compared to gas flow, split ratio, injection temperature, temperature program offset and column brand.
New Psychoactive Substances (NPS) are quickly developing to evade legislation, posing unprecedented challenges to public health and law enforcement authorities around the world. The aim of this work was to develop and validate a simple and reliable non-target gas chromatography/mass spectrometry (GC/MS) analytical method based on linear retention indexes for the expeditious identification of NPS without the need of analytical standards. The method was optimized and validated for 22 different drugs covering ten categories: phenethylamines (amphetamine, MDMA, methamphetamine, 25CNBOMe, 2-FA, 5-MAPB), “classic” drugs (cocaine, ephedrine, THC, heroine), synthetic cannabinoids (JWH-081, AM-2201, JWH-210, MAM-2201), piperazines (o-CPP, p-CPP), tryptamines (5-MeO-MiPT), synthetic cathinones (N-ethylpentylone), synthetic opioids (U-47700), aminoindanes (5-IAI), plant-based substances (Salvinorin-A) and “other” (methiopropamine). Three figures of merit (Selectivity, Precision and Robustness) were evaluated with retention index confidence intervals ranging from 0.5 to 20.6 i.u. and relative standard deviations in the range of 0.003% to 0.027% (repeatability) and 0.02% to 0.29% (intermediate precision). A general equation for estimating linear retention index variation as a function of retention time tolerance has been derived. This result in combination with a 2III6−3 fractional factorial design allowed to conclude column polarity to be only statistically relevant factor as compared to gas flow, split ratio, injection temperature, temperature program offset and column brand.
The episodic nature of natural selection and the accumulation of extreme sequence divergence in venom-encoding genes over long periods of evolutionary time can obscure the signature of positive ...Darwinian selection. Recognition of the true biocomplexity is further hampered by the limited taxon selection, with easy to obtain or medically important species typically being the subject of intense venom research, relative to the actual taxonomical diversity in nature. This holds true for scorpions, which are one of the most ancient terrestrial venomous animal lineages. The family Buthidae that includes all the medically significant species has been intensely investigated around the globe, while almost completely ignoring the remaining non-buthid families. Australian scorpion lineages, for instance, have been completely neglected, with only a single scorpion species (Urodacus yaschenkoi) having its venom transcriptome sequenced. Hence, the lack of venom composition and toxin sequence information from an entire continent's worth of scorpions has impeded our understanding of the molecular evolution of scorpion venom. The molecular origin, phylogenetic relationships and evolutionary histories of most scorpion toxin scaffolds remain enigmatic. In this study, we have sequenced venom gland transcriptomes of a wide taxonomical diversity of scorpions from Australia, including buthid and non-buthid representatives. Using state-of-art molecular evolutionary analyses, we show that a majority of CSα/β toxin scaffolds have experienced episodic influence of positive selection, while most non-CSα/β linear toxins evolve under the extreme influence of negative selection. For the first time, we have unraveled the molecular origin of the major scorpion toxin scaffolds, such as scorpion venom single von Willebrand factor C-domain peptides (SV-SVC), inhibitor cystine knot (ICK), disulphide-directed beta-hairpin (DDH), bradykinin potentiating peptides (BPP), linear non-disulphide bridged peptides and antimicrobial peptides (AMP). We have thus demonstrated that even neglected lineages of scorpions are a rich pool of novel biochemical components, which have evolved over millions of years to target specific ion channels in prey animals, and as a result, possess tremendous implications in therapeutics.
Nonalcoholic fatty liver disease Paredes, Angelo H; Torres, Dawn M; Harrison, Stephen A
Clinics in liver disease,
05/2012, Letnik:
16, Številka:
2
Journal Article
Recenzirano
As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although ...it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy.
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